|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 90 No. 2 (July 15), 1997:
pp. 489-519
REVIEW ARTICLE
Transcription Factors, Normal Myeloid Development, and Leukemia
By
Daniel G. Tenen,
Robert Hromas,
Jonathan D. Licht, and
Dong-Er Zhang
From the Hematology/Oncology Division, Department of Medicine, Beth Israel Hospital, Harvard Medical School, Boston, MA; the Hematology/Oncology Section, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN; and the Division of Molecular Medicine, Mt Sinai School of Medicine, New York, NY.
 |
INTRODUCTION |
TRANSCRIPTION FACTORS play a major role in differentiation in a number of cell types, including the various hematopoietic lineages.1-4 In the hematopoietic system, stem cells undergo a process of commitment to multipotential progenitors, which in turn give rise to mature blood cells. Although a number of transcription factors have been identified that play a role in the development of erythroid or lymphoid lineages,5-9 only in the past few years have those factors that influence development of myeloid cells been identified and studied. In particular, recent studies of the regulation of normal myeloid genes, as well as the study of leukemias, have suggested that transcription factors play a major role in both myeloid differentiation and leukemogenesis.10-12a To understand the process of normal myeloid differentiation, it is important to identify and characterize the transcription factors that specifically activate important genes in the myeloid lineage. These factors may play a role in acute myeloid leukemia (AML), in which this normal differentiation program is blocked. Finally, some of the transcription factor genes identified at the sites of consistent chromosome rearrangements in AML have now been shown to play a role in normal myeloid gene regulation.
The purpose of this review will be to summarize these recent data regarding myeloid gene regulation and the transcription factors mediating this process to understand normal myeloid development and leukemia. Emphasis will be placed on the identified or potential role of these factors in leukemia; we will focus on how alteration of myeloid transcription factors (changes in expression and structure) could lead to alterations in normal function in myelopoiesis, leading to a block in differentiation. In addition, we will discuss those factors that are involved in normal human myeloid maturation or human leukemia. Although this review will of necessity discuss different classes of factors, it does not aim to be an exhaustive compilation or listing of different factors and does not intend to be historical. Rather, it will attempt to highlight how recent findings can help to explain normal myeloid development and myeloid leukemia and will focus on certain examples to make important general points. In addition, this review will focus on early events in myeloid development and only briefly mention transcription factors involved in activation of mature myeloid cells. Finally, because there have been several recent reviews on hematopoietic factors in general, GATA, AML1, and the retinoic acid receptors, we will attempt as much as possible not to repeat what has been presented in these reviews.3,4,10-19 Some of the key issues that we will attempt to address in this review are the following: (1) How is gene expression restricted to myeloid cells? (2) How is the temporal expression of myeloid genes controlled? (3) Which transcription factors are thought to be necessary for myeloid development based on knockout and/or inactivation studies and which are thought to be necessary based on their redundancy? (4) If certain transcription factors are expressed in myeloid and nonmyeloid cells, why are certain target genes expressed in myeloid cells specifically? (5) How does a common progenitor cell become one type (myeloid) rather than another?
Currently, models have been advanced proposing that hematopoietic lineage determination is driven extrinsically (through growth factors, stroma, or other external influences),20,21 intrinsically (as described in stochastic models),22 or both.23 Our working hypothesis is that, regardless of whether the environmental or stochastic models are invoked, transcription factors are the final common pathway driving differentiation and that hematopoietic commitment to different lineages is driven by alternative expression of specific combinations of transcription factors, which often induce expression of growth factor receptors or growth factors. The transcription factors are often activated in positive autoregulatory loops, helping to explain the irreversible differentiation process found in human hematopoiesis. Experimental support of the hypothesis that transcription factors are the nodal decision points for myeloid differentiation include the observations that many genes cloned at the site of leukemic translocation breakpoints are transcription factors,11,12,24 genes isolated by their regulation of a phenotype (such as differentiation) are transcription factors,25 and, finally, knockouts of these transcription factors show gross defects in myeloid development.3,26-28
| |
METHODS USED TO IDENTIFY AND STUDY MYELOID TRANSCRIPTION FACTORS |
Our understanding of myeloid factors has been brought about by a number of different methods. Initially, myeloid factors were identified by investigations of known transcription factors, particularly oncogenes; examples include myb, myc, and the homeobox genes.12a Similarly, a number of factors have been isolated using hybridization and/or polymerase chain reaction (PCR) methods based on similarity to known genes, such as MZF-1, with subsequent studies investigating the normal and forced expression of these factors in myeloid cells.29-36 A second approach is subtraction hybridization or differential screening, which identified Egr-1 as a potential mediator of monocytic development.25 A third method has been identification of factors through the analysis of myeloid-specific promoters. Examples are PU.1 and C/EBP , and these studies will be described in further detail below. Finally, a number of myeloid transcription factors have been identified through their involvement in leukemias, either as a result of abnormal expression, such as PU.1,37,38 or through their involvement at the site of a consistent chromosome translocation (examples include AML139 and PLZF40; see Table 1).
Once identified, the role of these factors has been ascertained by a number of inhibitory studies. These include the use of antisense and competitor oligonucleotide techniques, which have shown the role of myc, myb, MZF-1, and PU.1 in myeloid development.41-44 A limited number of studies have used a trans-dominant mutant approach and have been used to demonstrate the role of the retinoic acid receptor in myeloid development and of PU.1 in activation of specific gene targets.45-47 Finally, the technique of gene disruption (knockout) has recently been used to investigate the role of specific factors in myeloid development.3,7,26-29,48-50 A recent review has focused on the effects of these knockout studies on hematopoiesis in general3; therefore, we will discuss them only as they relate to myeloid transcription factors.
| |
HOW DO MYELOID PROMOTERS WORK? WHAT ARE GENERAL RULES SO FAR? |
Many myeloid promoters appear to differ from what has been described previously for tissue-specific promoters.51 In general, a relatively small upstream region (usually a few hundred basepairs) is capable of directing cell-type-specific expression in tissue culture studies, although it appears that additional elements are necessary for position independent, high-level expression in a chromosomal locus (Fig 1). For example, almost all of the specificity and activity detected in transfection of tissue culture cells by the macrophage colony-stimulating factor (M-CSF) receptor, granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor , and granulocyte colony-stimulating factor (G-CSF) receptor promoters are contained within 80, 70, and 74 bases of the major transcription start sites, respectively,52-54 and similar results have been obtained with the promoters for myeloid transcription factors such as PU.1.55,56 Although most of these promoters direct lineage and developmental specific expression, in general they lack a TATA box or defined initiator sequence. Interestingly, many myeloid promoters have a functional PU.1 binding site upstream of the transcription start site at a location corresponding to one similar to that of a TATA box. Because PU.1 can bind to the TATA binding protein (TBP) in vitro,57 one mechanism by which PU.1 could activate a whole class of myeloid promoters is by recruiting TBP, the primary component of the basal transcription factor TFIID, and the rest of the transcriptional apparatus. Consistent with this mechanism are studies showing that mutation of a PU.1 site in the Fc R1 promoter can abolish myeloid-specific expression, and replacement of this mutant site with a TATA box can restore myeloid expression.58 Other factors involved in myeloid gene regulation, including Sp1, C/EBP, and Oct-1, have all been shown to interact with TBP,59-61 and these interactions could also help mediate recruitment of the basal transcription machinery. Finally, whereas some of these TATA-less and initiator-less myeloid promoters have multiple transcriptional start sites,55,62 others appear to have a single strong start site.63,64 The mechanism for how the start sites are determined in these promoters is unknown.
View larger version (14K):
[in this window]
[in a new window]
| Fig 1.
Specificity of the human M-CSF receptor promoter is mediated by combinatorial activity of factors in myeloid cells. The activity and specificity of the human M-CSF receptor promoter in transient transfection studies is mediated by the 50-bp region lying between bp -88 and -40 relative to the major transcription start site in monocytic cells.52,117,215 Shown are the binding sites for C/EBP, AML1, and PU.1, all of which are important for M-CSF receptor promoter activity. In the hematopoietic system, C/EBP is myeloid specific, AML1 is expressed in all white blood cells, and PU.1 is B-cell- and myeloid-specific, so therefore the major cell type in which all three are expressed is myeloid cells. In addition, C/EBP and AML1 can physically interact and synergize to activate this promoter.215 Others have shown using other promoters that C/EBP proteins can synergize with PU.1.88 Also shown is CBF , which forms a heterodimer with AML1 and augments its ability to bind to DNA.
|
|
Consistent with their lack of a TATA box, these promoters often are dependent on a functional Sp1 site, which can interact not only with the TATA binding protein, TBP, as well as a TBP-associated factor, TAF110.59 These Sp1 sites not only mediate activity, but also specificity and inducibility with differentiation.65-67 How the Sp1 factor mediates this specificity is not clear, but in one case Sp1 binds to its myeloid target in vivo in myeloid cells only,65 and in another, increased relative expression in myeloid cells of a phosphorylated form of Sp1 that shows markedly increased binding to its DNA target site is observed.66 Although Sp1 is ubiquitous, it is preferentially expressed in hematopoietic cells.68 Differential expression in distinct hematopoietic lineages has not been explored. In addition, Sp1 can mediate responses to retinoic acid, thyroid hormone, and retinoblastoma protein, all of which may influence myeloid differentiation.69-72 Finally, it has been recently shown that Sp1 belongs to a family of related factors and that at least one of these, Sp3, may mediate repression of target genes.73,74 Sp1 can also cooperate in repression with GATA-1,75 and this interaction could potentially repress myeloid targets in erythroid cells (see below).
Several of the myeloid promoters appear to have GATA sites that can bind GATA proteins specifically in gelshift assays. However, mutation of GATA binding sites in the CD11b76 or PU.155 promoters does not lead to significant loss of promoter function. Coexpression of either GATA-1 or GATA-2 leads to a slight downregulation (2-fold) of these promoters. Interestingly, there is a functional GATA-1 site in the promoter for the platelet-specific integrin IIb that is located at a position almost identical to that of the nonfunctional GATA site found in the myeloid integrin CD11b,77 suggesting evolutionary conservation of binding sites in related integrin promoters, but not function. The differences between the ability of GATA-1 to activate promoters such as IIb in erythroid or megakaryocytic cells, in which GATA-1 is thought to play an important role in lineage development and not in myeloid cells, may be due to cell-type-specific modifications of GATA and/or interactions with other transcription factors. In addition, GATA-1 is not expressed at significant levels in myeloid cells, and both GATA-144 and GATA-278 are downregulated in myeloid development. These results are consistent with the preservation of myeloid cell development in mice with targeted mutations of GATA-1.5 In contrast to monocytic and neutrophilic cells, high levels of GATA-1 are detected in eosinophils,79 but to date functional GATA sites have not been detected in eosinophil promoters. In summary, it appears that GATA proteins do not play an important positive role in myeloid development; indeed, downregulation may be critical for myeloid maturation.44,80,81
As noted above, almost all myeloid promoters have a functional PU.1 site close to the transcription start site. There are a number of interesting exceptions to this rule. The CD14 promoter has a TATAA-like sequence and does not have a functional PU.1 site in its promoter.66 This promoter region is highly active and cell-type-specific in transient assays66 but not in transgenic mice.82,83 This scenario is somewhat similar to that of chicken lysozyme, which lacks a PU.1 site in its promoter but contains one in an enhancer located 2.7 kb upstream and which is part of a genomic fragment that is capable of high-level specific expression in mice.84,85 Whether other myeloid promoters that lack PU.1 sites will turn out to have PU.1-containing enhancer elements located several kilobases from the promoter remains to be determined.
Another set of myeloid genes that appear to have TATAA boxes are the primary granule protein promoters, including myeloperoxidase,86,87 neutrophil elastase,87,88 proteinase 3,89 and cathepsin G.90 At least three of these have been noted to have functional PU.1 sites, and in this class of genes PU.1 plays an important role, but perhaps has a different mechanism than other myeloid genes in which there is no TATAA box. At this point it is not clear what other common factors account for the distinct pattern of expression of these genes, in which mRNA is dramatically upregulated at the promyelocytic stage and then rapidly downregulated with further myeloid development. It has also been observed that a number of these same primary granule myeloid promoters (cathepsin G, myeloperoxidase, neutrophil elastase, aminopeptidase N, c-fes, and MRP8) contain a common sequence CCCCnCCC.91 Recently, a protein binding to this site has been described, and mutations of this site in the proteinase-3 promoter that abrogate binding of this factor lead to a significant loss in promoter function.89 Therefore, identification of this protein may lead to important understanding of the regulation of this whole family of myeloid genes.
In contrast to the primary granule protein genes, most other myeloid-specific genes are upregulated during the course of myeloid development and are expressed at highest levels in mature myeloid cells. Examples include key receptors, such as the G-CSF receptor92 and CD11b,93,94 as well as critical transcription factors, such as PU.1.44,95 In some cases, there are emerging clues into the mechanisms of upregulation during differentiation. For example, the upregulation of the CD14 promoter during vitamin D3-induced monocytic differentiation is mediated by an Sp1 site,67 and recently a novel transcription factor has been described that mediates upregulation of CD11b promoter activity during 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced differentiation of myeloid cell lines.96 The binding site for this factor is shared by the three leukocyte integrin promoters. The factor identified, MS-2, like Sp1, is not specific for myeloid cells. In other cases, the promoter elements and transcription factors mediating upregulation during myeloid differentiation have not been well defined. It should be noted that the transcription factors critical for upregulation during myeloid development versus those invoked during activation of mature myeloid cells may well be distinct. For example, the macrophage scavenger receptor has motifs mediating lineage specificity (including a PU.1 site) and a distinct element mediating upregulation of stimulated macrophages (through an AP-1/ets site).97 Similarly, distinct elements mediating lineage upregulation of the interleukin-1 (IL-1) promoter in macrophage lines have been described.47,98,99
Functionally important transcriptional regulatory elements have been described in the 5' untranslated regions of a number of genes,100,101 and several myeloid promoters also contain important functional sites in their 5' untranslated region. The human and murine PU.1 promoters are almost totally conserved in their 5' untranslated region, and both contain a functional PU.1 site.55 In the case of the human and murine G-CSF receptor promoters, conservation in this region is mainly limited to the PU.1 site found there.53
| |
TRANSGENIC STUDIES |
Often myeloid regulatory factors have been identified through the investigation of myeloid-specific promoter elements in studies involving transient transfection studies in tissue culture cell lines. In transgenic mice, other regulatory elements, such as locus control elements, are very important.102 A number of myeloid promoters have worked to some extent in transgenic studies involving the expression of heterologous genes in myeloid cells. In some instances, there is variability of levels of expression and significant position dependence. For example, the proximal 1.5 kb of the gp91-phox gene, normally expressed at high levels in granulocytes, targeted reporter expression to a small subset of monocytic cells only, and most monocytes and neutrophils did not express the transgene.103 In other examples, the responsible regulatory elements have not yet been defined in detail. These studies include human c-fes/fps,104 chicken lysozyme,85,105 or human cathepsin G,90 in which the investigators reported high-level, properly regulated transgene expression. In these studies, relatively large pieces of DNA (6 to 21.5 kb) were used that included the gene itself as the reporter. In some instances, the expression patterns of the transgenes were not described in detail, but were stated to be specific for macrophages and neutrophils, respectively. Examples include those involving a 5-kb portion of the monocytic M-CSF (CSF-1) receptor promoter, which was reported to target macrophages,106,107 and the MRP8 promoter, which was used to express bcl-2 in neutrophils.108 The MRP8 promoter has also been used to induce expression of a PML/RAR transgene in myeloid cells, resulting in a high percentage of expressing transgenic lines, altered granulocytic differentiation, and, in some animals, an acute leukemia resembling human acute promyelocytic leukemia.109 A recent study has shown that the human lysozyme promoter can direct reporter gene expression in macrophages.110
A number of studies have looked at the ability of myeloid integrin promoters to direct the expression of reporter genes in transgenic studies.111,112 The CD11b promoter is capable of driving high-level expression of a reporter gene in myeloid cells at levels comparable to the endogenous CD11b promoter. This promoter construct is position-dependent, perhaps explaining why another group did not observe similar levels of expression.112 Although in these studies the activity of the promoter was highest in mature myeloid cells, this promoter construct has also been used to direct expression of the t(15:17) PML/RAR fusion protein in early myeloid cells.113 The reason for these differences is not clear, but may reflect a significant amount of position dependence on promoter activity and specificity. Attempts to direct expression of reporter genes into early myeloid cells using promoters such as CD3483 and c-kit114 have not been successful. However, recent reports suggest that upstream regions of the cathepsin G115 and MRP8108,109 genes may be useful in directing expression of an inserted cDNA into promyelocytes. Many of the promoters used in these studies, like most myeloid-specific genes, lack a TATAA box,63,76 and previous studies using transient transfections in tissue culture cells have shown the role of PU.1 in the myeloid specificity of the promoters (Table 2). Of the myeloid genes that have been shown to function in transgenic studies to date, several of them, including CD11b,116 the M-CSF receptor,117 the chicken lysozyme enhancer,84 and c-fes,118,119 have important functional PU.1 sites. A recent study has confirmed the importance of the PU.1 site in macrophage expression of the macrophage scavenger receptor.120 These studies strongly suggest that PU.1 will in general be a critical factor in directing myeloid expression in transgenic studies.
In summary, it appears from the transgenic studies that myeloid promoters can drive expression in monocytic and neutrophilic cells in transgenic mice and that the PU.1 site is likely to be critical. However, the details of the other critical elements necessary for myeloid-specific and position-independent expression are not defined yet, and much work needs to be performed in this area in the future.
| |
GENE THERAPY APPLICATIONS OF MYELOID PROMOTERS |
An exciting prospect would be to use the myeloid regulatory elements to target given genes to proper hematopoietic compartments for gene therapy applications, particularly in terms of directing macrophage expression of enzymes involved in glycogen storage diseases.121 Myeloid promoter elements may be useful for viral vectors, especially adeno-associated virus (AAV), because, at least in transient assays, very small DNA fragments of a few hundred basepairs direct activity that is as high and as specific as much larger fragments. A note of caution is that larger elements or a combination of promoter and upstream elements (locus control regions) may be necessary, as noted above from the description of transgenic studies. Very few reports on the use of myeloid elements in gene therapy vectors have been reported. In one study, the CD11b promoter failed to direct significant reporter expression when incorporated into a retroviral vector,122 but a second study showed the same promoter directing significant amounts of glucocerebrosidase mRNA and enzymatic activity in myeloid cell lines and in bone marrow.123 Again, the reason for the discrepancies observed between these two studies using a similar promoter is not clear, and much more work needs to be performed in this area of research.
| |
PU.1 (Spi-1) AND OTHER ets FACTORS |
PU.1: A master regulator of myeloid genes.
Recent studies have focused on PU.1 as a major regulator of myeloid development.26,44,161 PU.1 is the product of the Spi-1 oncogene identified as a consequence of its transcriptional activation in Friend virus-induced erythroleukemias.14,37,38,124 The role of PU.1 in the malignant transformation of the proerythroblast was confirmed by subsequent studies. Overexpression of PU.1 from a retroviral construct in long-term bone marrow cultures is able to stimulate the proliferation of proerythroblast-like cells that differentiate at a low frequency into hemoglobinized cells,125 and overexpression in transgenic mice can also induce erythroleukemia.126 Moreover, PU.1 antisense oligonucleotides reduce the capacity of Friend tumor cells to proliferate.127 Taken together, these data suggest that deregulation of PU.1 increases the self-renewal capacity of erythroid precursor cells and blocks their differentiation. Furthermore, it shows the importance of proper regulation of PU.1 in the hematopoietic system.
PU.1 is a member of the Ets transcription family.124 Ets factors all contain a characteristic DNA binding domain of approximately 80 amino acids.14,128,129 PU.1 and the related Ets family member Spi-B130 form a distinct subfamily within the larger group of Ets proteins, with very distinct structure, patterns of expression, binding specificity, and functions that are nonoverlapping with other members of the Ets family. The PU.1 protein consists of 272 amino acids, with the DNA binding domain located in the carboxyl terminal part of the protein, whereas the amino terminus contains an activation domain that has been implicated in interactions with other regulatory proteins.57,124,131,132 The structure of the DNA binding domain has been recently determined and demonstrates a winged helix-turn-helix motif.133
PU.1 shows specific patterns of hematopoietic expression. PU.1 is expressed at highest levels in myeloid and B cells, but not in T cells.37,95,124 During hematopoietic development, PU.1 mRNA is expressed at low levels in murine ES cells and human CD34+ stem cells and is specifically upregulated with myeloid differentiation.44 The timing of this upregulation coincides with the first detection of early myeloid maturation, suggesting that this increase in expression may be an important process in myeloid development, and inhibition of PU.1 function at this juncture can block myeloid progenitor formation.44 These findings were confirmed by another report showing that PU.1 is expressed in the earliest Go CD34+ stem cells and upregulated as single CD34+/CD38- cells developed into myeloid colonies.134 Studies in both primary CD34+ cells and human leukemic cell line models suggest that PU.1 mRNA and DNA binding activity do not increase further with subsequent myeloid maturation from the promyelocytic to more mature stages,44,95 but these studies do not preclude the possibility that the high levels of mRNA observed in human monocytes and neutrophils95 are a result of subsequent final maturation and/or activation. Although initially thought to be B-cell and monocyte specific,124,135 high levels of both PU.1 mRNA and DNA binding activity have been subsequently found in neutrophils.95 PU.1 mRNA has also been detected in human eosinophils (S.J. Ackerman and D.G. Tenen, unpublished observations). In murine Friend erythroleukemia cells, PU.1 is downregulated during chemically induced erythroid differentiation.127,136,137
These expression studies suggest that regulation of PU.1 mRNA may play a significant role in the commitment of early multipotential progenitors to the myeloid lineages, as well as in the further differentiation and maturation of these cells. Characterization of the murine and human PU.1 promoters shows that a highly conserved region surrounding the transcription start sites can direct myeloid-specific activity in transient transfection studies. The important functional sites identified thus far in the promoter, an octamer site at bp -54, an Sp1 site at bp -39, and a site for PU.1 itself at bp +20, are conserved in the two species. In B cells, the octamer site plays a major role in PU.1 expression,56,138 whereas in myeloid cells the PU.1 site is the most important for function of the promoter.55 This study suggests the presence of a positive feedback mechanism in the regulation of the PU.1 promoter similar to that shown for another Ets family member, Ets-1.139 Such autoregulation of transcription factors could play a major role in commitment and differentiation of hematopoietic multipotential progenitor cells (see below). The PU.1 promoter also contains a site that can bind GATA proteins, but no binding could be detected using nuclear extracts from myeloid cell lines, and cotransfection of either a GATA-1 or GATA-2 expression construct repressed the PU.1 promoter twofold. Important unanswered questions are whether GATA proteins affect PU.1 expression in multipotential progenitors44 or in early erythroid cells, in which PU.1 is repressed in the course of differentiation.136,137,140 Finally, although the elements described above direct expression of PU.1 in tissue culture cells, as much as 2 kb of upstream murine DNA sequence failed to direct expression of a reporter cDNA in spleen or peritoneal macrophages in transgenic studies, so other elements are required for high level expression in the chromosomal context.83
PU.1, like other Ets factors,128 was first noted to bind to a sequence characterized by a purine-rich core (GGAA), hence its name.124 However, the DNA binding specificity of PU.1 appears to be quite distinct from that of other Ets factors. For example, PU.1 and Spi-B bind to the CD11b PU.1 site, but not the other Ets family members Ets-1, Ets-2, Elf-1, or Fli-1.44 In addition, it is not possible to predict PU.1 binding by observation of a 5'-GAGGAA-3' sequence. For example, there are three such sequences in the M-CSF receptor promoter, and PU.1 does not bind to any of them with high affinity. Instead, PU.1 binds to the nearby sequence 5'-AAAGAGGGGGAGAG-3'.117 This example is consistent with previous work indicating that binding of PU.1 and other Ets factors is dependent on sequences outside the GGAA core.141 In addition, many functional PU.1 binding sites in myeloid promoters have a string of adenosine residues immediately 5' of the GA core.54,116,117,137 These results are consistent with a recently described consensus sequence for PU.1 binding.118 The availability of an x-ray crystallographic structure for PU.1133 will assist in further studies of PU.1 binding specificity. In summary, PU.1 is distinct from other Ets factors in DNA binding specificity. Identification of the transactivation domain of PU.1 has been relatively difficult because PU.1 acts as a weak transactivator; indeed, most transactivation studies have required multiple PU.1 binding sites and used artificial promoter constructs.53,55,124,142 Studies using myeloid promoters have in general shown weak transactivations, on the order of twofold to fivefold.116,117 Recently, using multimerized reporter constructs, the transactivation domain of PU.1 was identified in the amino terminus.131 These studies defined multiple relatively weak transactivation domains; whether this indicates that each interacts with different proteins (see below) remains to be determined.
PU.1, like other Ets proteins, interacts with other transcriptional regulators. In B cells, PU.1 recruits a second, B-cell -specific DNA binding factor, NF-EM5 or Pip, to a site important for Ig  3' enhancer function.143-146 For this interaction, phosphorylation of a serine residue at position 148 is necessary.144 However, such interactions have not been shown previously to play a functional role in previously described myeloid targets of PU.1, such as CD11b and the M-CSF receptor, and mutation of Ser148 does not affect the ability of PU.1 to activate these myeloid promoters.116,117
As noted above, PU.1 can interact with TBP in vitro.57,132 An attractive hypothesis is that PU.1 may recruit the basal transcription machinery to myeloid promoters, which in general lack TATAA boxes, but the functional significance of this interaction is not known at this time. Similarly, these same studies showed that PU.1 can interact physically with RB. It has been shown that hypophosphorylated RB can negatively regulate the activity of another Ets factor, Elf-1, in the course of T-cell activation.147 Because RB becomes hypophosphorylated during myeloid differentiation,148,149 it possibly could regulate PU.1 function in these cells. Experiments to date have failed to show an effect of RB on PU.1 function on myeloid promoters,83 although it has been shown that RB can repress PU.1 function on an artificial promoter.132 A recent study using a protein interaction screen has identified a number of proteins that can bind to PU.1, although the functional consequences of these interactions remains to be determined.142 One of these is HMG(I)Y, which has been shown to augment the ability of the Ets factor Elf-1 to activate the IL-2 receptor chain.150 To date, similar experiments with HMG(I)Y have failed to show binding to myeloid targets such as the M-CSF receptor or GM-CSF receptor promoters or to augment the ability of PU.1 to activate these promoters. Another factor cloned in this study and shown to bind to PU.1 is NF-IL6 (same as C/EBP ); in this case, it was shown that PU.1 and C/EBP could cooperatively activate an artificial reporter plasmid. These findings are interesting because they suggest that PU.1 might also interact with C/EBP (see below). Similarly, in another study, PU.1 has been shown to interact with another basic leucine zipper (BZIP) transcription factor, c-Jun.151 Finally, PU.1 has been shown to functionally interfere with steroid hormone gene activation, and steroid hormone receptors can inhibit PU.1 transactivation function.152 Of particular relevance to myeloid development is the fact that these interfering effects were seen with the retinoic acid receptor.152 However, the functional significance with respect to myeloid development of all of these interactions is not known.
Ets family members have been shown to play an important role in several signal transduction pathways.153-156 PU.1 is phosphorylated in vitro by casein kinase II and JNK kinase, but not by ERK1 (MAP) kinase.157 A recent study has shown that lipopolysaccharide (LPS) can activate casein kinase II and phosphorylation of PU.1 in LPS-stimulated macrophage lines.158 The LPS stimulation of PU.1 transactivation of a reporter construct was abolished by a serine to alanine mutation of residue 148, suggesting that stimulation of macrophages with LPS leads to increased phosphorylation and activity of PU.1. The same PU.1 phosphorylation site has been shown to be important for B-cell gene activation (see above). A recent study implicated PU.1 in M-CSF-induced proliferation of murine macrophages, and this effect was abrogated by mutating two potential phosphorylation sites (Ser41 and Ser45) in the transactivation domain of PU.1 that are distinct from the postulated site of LPS stimulation at Ser148.159 Finally, a recent study suggested that there may be differences in PU.1 phosphorylation between myeloid cells and B cells, but not during myeloid commitment of multipotential progenitors.160
A number of studies have addressed PU.1 function in myeloid cells by inhibiting its function. Addition of competitor oligonucleotides to human CD34+ cells specifically blocked myeloid CFU formation.44 The inhibition was only observed if the competitors were added very early during GM-CSF-induced myeloid maturation, before the upregulation of PU.1 expression. Several groups have addressed the function of PU.1 on murine development using targeted disruption of the PU.1 gene.26,161 One group reported that PU.1 -/- embryos died in utero, usually at day E16.26 These animals demonstrated a variable anemia, but no production of any type of white blood cells, including monocytes, neutrophils, and B cells, as might be expected based on the expression of PU.1 and its known target genes. The concomitant failure to produce T cells in the -/- animals was surprising, given that PU.1 has not been known to be expressed in this lineage (see above). These studies suggested that the defect was either due to a block of a very early multilineage progenitor cell or that T-cell development is dependent on the presence of macrophages and/or B cells.26
A second PU.1 knockout animal yielded a phenotype with some distinct differences.161 The PU.1 -/- animals in this case were viable at birth and could be kept alive for days by housing them in a sterile environment with the administration of antibiotics. These animals also lacked monocytes and mature B cells, but were capable of producing B-cell progenitors. Several days after birth, T cells and cells resembling neutrophils in the peripheral blood were detected. In this case, the findings suggested a role for PU.1 in B-cell and monocytic development, which is more in keeping with its known pattern of expression and its known gene targets. Although neutrophilic cells were observed, they were Mac-1-negative and reduced in number, suggesting that targeting PU.1 results in a partial defect in neutrophil development. The reason for these marked differences between the two knockout phenotypes is not known at this time, but will be important to determine in that the former knockout model suggests that PU.1 plays an important role in multipotential cells,26 whereas the latter suggest a more limited role in B-cell and myeloid development.161 In vitro differentiation of PU.1 -/- ES cells does not produce macrophages and points to the M-CSF receptor as a major target for PU.1 in understanding its effect on myeloid differentiation.162,163
Consistent with the finding that PU.1 has a major role in myeloid development has been the identification in the past three years of multiple myeloid genes regulated by PU.1 (Table 2). In transfection studies, PU.1 regulates a number of genes that appear as late markers of myeloid cells (Table 2). In addition, PU.1 sites are critical for the activity of a number of myeloid CSF receptor promoters, including the M-CSF receptor,117,164 the GM-CSF receptor ,54 and the G-CSF receptor promoter.53 Quantitative studies will be needed to establish whether hematopoietic cells in PU.1 knockout animals have decreased or absent expression of these three myeloid CSF receptors. If so, the role of expression of these receptors in myeloid development can be tested by restoring their expression singly or in combination in these PU.1 -/- animals. As noted above, studies in PU.1 -/- ES cells have confirmed that CD11b and the M-CSF receptor are major targets for PU.1.162,163 In addition to transactivating the promoters of the genes cited above, it is possible that PU.1 has other mechanisms of action. Recently, it was noted that PU.1 (but not Spi-B or other Ets factors) can bind RNA, suggesting that it could possibly play a role in posttranscriptional regulation.165 The biologic significance of these observations remains to be determined.
Although PU.1 was first isolated as a gene activated in murine erythroleukemia,37 so far it has not been implicated in the pathogenesis of human leukemias. The PU.1 gene has been mapped to 11p11.22, not a frequent site of chromosomal translocations found in human leukemia. PU.1 expression in leukemic myeloid lines is not higher than that observed in primary myeloid cells,95 and a recent survey of primary human leukemias found no significant discordance between PU.1 expression in leukemic samples and that predicted by the apparent differentiation stage of the leukemic cells (M.T. Voso, unpublished observations). However, no studies to date have addressed whether PU.1 is mutated in human leukemias.
Other Ets factors and myeloid development.
Spi-B was isolated by hybridization with a PU.1 cDNA probe and, together with PU.1, forms a distinct subfamily within the Ets factors.130 In contrast to other Ets proteins,44 Spi-B can bind to many of the targets for PU.1 and can transactivate many of these myeloid genes.55,95 However, the observation that PU.1 knockout mice failed to produce certain myeloid lineages suggested that Spi-B might be expressed quite differently from PU.1. This was confirmed by studies showing that Spi-B is not expressed at significant levels in myeloid cells, suggesting that its role in myeloid differentiation and function is likely to be limited.55,95 Recently, it has been shown that the binding specificity of Spi-B is very similar but not identical to that of PU.1,118,166 and perhaps this can also contribute to the differences in function of these two factors. In addition, Spi-B and PU.1 are phosphorylated by different kinases.157
To date the role of other Ets factors in myeloid development has not been well defined. A number of other Ets factors are expressed in myeloid cells, including Ets-2, Fli-1, and Elf-1167,168 (D.E.Z. and D.G.T, unpublished observations). Ets-2 is capable of transactivating the murine M-CSF receptor promoter,169 but targeted disruption of the Ets-2 gene did not affect the ability of ES cells to form macrophages in vitro,163 suggesting that Ets-2 does not play a necessary role in myeloid development. Ets-2 may play an important role in activation or signaling in macrophages.107,156,164 The ubiquitous Ets protein GABP is important for the activity of the CD18 protein and can functionally cooperate with PU.1.170 GABP from myeloid cells can also bind to the neutrophil elastase promoter and cooperates with c-myb and C/EBP to transactivate this promoter in nonmyeloid cells (A. Rosmarin, unpublished observations). Recently, another ubiquitously expressed Ets protein, TEL, was isolated from a patient with chronic myelomonocytic leukemia as a fusion protein with the platelet-derived growth factor (PDGF) receptor.171 TEL can also form a fusion protein with AML1 in a large percentage of cases of pre-B-cell acute lymphoblastic leukemia (ALL).172 At this time, the precise role of TEL in myeloid development and in the pathogenesis of myeloid leukemia is not known.173
| |
C/EBP, A REGULATOR OF GRANULOCYTIC DEVELOPMENT |
C/EBP (CCAAT/enhancer binding protein; now known as C/EBP) was isolated as a rat liver protein that bound to viral enhancer sequences174,175 and is a member of one of several leucine zipper transcription factor families, including the fos/Jun family and the ATF/CREB family.176-178 C/EBP binds as a homodimer or heterodimer with other C/EBP proteins or other transcription factors and has been shown to regulate a number of hepatic and adipocyte genes. C/EBP is upregulated and plays an important role in adipocyte differentiation and in this cell type functions in fully differentiated, nonproliferative cells; inhibition of C/EBP blocks differentiation; and expression of C/EBP induces differentiation.179,180 Indeed, several studies have indicated that C/EBP can act as a general inhibitor of cell proliferation and in this respect resembles a tumor suppressor.181-183 C/EBP is part of a family of leucine zipper transcription factors, including C/EBP and C/EBP, that heterodimerize and are differentially regulated during adipocyte differentiation.179,184,185 Another very interesting C/EBP gene, C/EBP , was very recently isolated and shown to be preferentially expressed in myeloid cells.186,187 Both C/EBP and C/EBP have single mRNAs that can encode transcriptionally active and repressive forms, depending on the usage of alternative start AUG codons in the same reading frame.188,189 In addition, another C/EBP family member, CHOP-10, can dimerize with C/EBP proteins to inhibit transcriptional activation and is found at a translocation breakpoint in liposarcomas.190,191 Of note is that CHOP can specifically block C/EBP activity and induce increased apoptosis of myeloid 32D cells.191
In murine adipocyte cell lines, C/EBP is transcriptionally upregulated (and C/EBP is downregulated) with adipocyte differentiation and binds to its own promoter.192 In addition, c-myc overexpression can block differentiation of adipocytes, possibly by repressing the C/EBP promoter.193 Interestingly, although both murine and human C/EBP promoters are autoregulated, the mechanisms of autoregulation are different. The murine C/EBP promoter has a binding site for C/EBP.192 The human C/EBP promoter does not conserve the C/EBP binding site found in the murine promoter, and the autoregulation is indirect and mediated by the action of C/EBP on a helix-loop-helix protein, upstream stimulatory factor (USF).194 Studies of C/EBP promoter analysis in myeloid cells have not been reported.
Whereas the C/EBP proteins are expressed in a number of different tissues, their expression in the hematopoietic system may be limited to myeloid cells. It has shown that C/EBP is specifically expressed in human myelomonocytic cell lines and not in human erythroid, B-cell, and T-cell lines,195 consistent with the myeloid-specific expression previously noted for avian C/EBP.196-199 In studies of murine 32D cells and human leukemic lines, such as HL-60 and U937 cells, the C/EBP proteins showed a pattern of expression quite different from that observed in adipocytes.195,200 In these studies, C/EBP was observed to be highly expressed in proliferating myelomonocytic cells upon induction of differentiation and downregulated with maturation, whereas C/EBP and C/EBP were upregulated. However, recent Northern blot analysis of human primary CD34+ cells shows that C/EBP expression is maintained during granulocytic differentiation but is markedly downregulated with monocytic or erythroid differentiation. In addition, Northern blot analysis of mature peripheral blood neutrophils shows very high levels of C/EBP mRNA, which was completely undetectable in adherent peripheral blood monocytes (H. Radomska and D.G.T., manuscript submitted). In addition, C/EBP was noted to be upregulated as single CD34+/CD38- cells were differentiated into granulocytic colonies; no such upregulation was observed during colony-forming unit-macrophage (CFU-M) colony formation.134 These studies point to a role of C/EBP in neutrophilic but not monocytic lineage development.
As noted above, C/EBP was the first protein noted to have the leucine zipper motif.176,201 The leucine zipper consists of repetitive leucine residues spaced every 7 amino acids that results in an helical amphipathic structure with hydrophobic and hydrophilic faces on each side of the helix. Just amino terminal to the zipper is a basic region that is highly positively charged and directly interacts with DNA. The leucine zipper is directly involved in homodimerization and heterodimerization. C/EBP, C/EBP, and C/EBP are strongly similar in their C terminal basic region and leucine zipper domains and diverge in the N-terminal transactivation domain.61,179,184,202,203 Adding to the complexity, other DNA binding proteins, including CTF/NF-1204 and NF-Y (also known as CBF and CP1),205-207 can bind to CAAT containing sequences. C/EBP binding sites consist of two half sites, but even the sequence CCAAT was not always required for binding. Despite the high degree of similarity of the carboxyl terminal basic-zipper DNA binding domain, C/EBP and C/EBP can bind with vastly different affinities to the same promoter site.208 The consensus binding site for C/EBP has been recently determined using PCR binding site selection.209
In addition to other members of the C/EBP family, the C/EBP proteins can interact with a number of transcription factors, including NF-B and Rel proteins,210,211 members of the CREB/ATF family,98,178 Sp1,212 RB,213 and members of the fos/jun zipper family.214 The amino terminal region of C/EBP has been shown to physically interact with TBP.61 As noted above, C/EBP has been shown to interact with PU.1,142 and PU.1 can physically interact with C/EBP83 and C/EBP as well (P. Auron, unpublished observations). As noted above, C/EBP and C/EBP are most similar in their carboxyl terminal basic-zipper DNA binding domain and less so in the amino terminus, perhaps explaining why they can also show very different abilities to interact with other proteins.212 Another functionally important interaction of relevance to myeloid gene regulation is that between C/EBP and AML1, which is important for M-CSF receptor promoter function in transfection studies (see below).215 Recently, it has been shown that the underphosphorylated form of the retinoblastoma (RB) protein can interact physically with C/EBP proteins to increase DNA binding and transactivation of target genes during adipocyte differentiation.216 As RB becomes underphosphorylated with myeloid differentiation,148,149 it could positively regulate C/EBP-induced granulocytic maturation.
Recently, lines of mice harboring a knockout of the C/EBP gene were generated.217,218 Heterozygous mice are outwardly normal, but homozygous mice die within the first few hours after birth of impaired glucose metabolism; their viability can be extended to about 1 day with injections of glucose. The mice are unable to properly synthesize and mobilize glycogen and fat. Analysis of the hematopoietic system in embryonic and newborn mice has demonstrated a significant defect in production of granulocytic cells.28 Newborn knockout (-/-) animals do not produce any mature neutrophils, which comprise 90% of the peripheral blood white blood cells of newborn heterozygote (+/-) or wild-type (+/+) mice. Cells that appear to be immature myeloid cells are observed in the peripheral blood. These cells stain with Sudan black, a characteristic of myeloid cells, and have increased myeloid CFU potential compared with those from heterozygote blood. Interestingly, many cells in the CFU from the knockout blood are immature in morphology as well, similar to what is observed in CFU from leukemic cells. Eosinophils are also not observed, but all of the other lineages, including peripheral blood monocytes and peritoneal macrophages, red blood cells, platelets, and lymphoid cells, appear quantitatively unaffected. Fluorescence-activated cell sorting (FACS) analysis in embryonic and newborn animals confirmed that myeloid markers (Mac-1 and Gr-1) were greatly reduced, with normal B- and T-cell subsets. Expression of the G-CSF receptor mRNA was profoundly and selectively reduced, whereas that of M-CSF receptor and GM-CSF receptor , c, and IL3 were all comparable to wild-type. Interestingly, a fourfold increase in mRNA for Epo receptor was detected, although whether this is due to a negative effect of C/EBP on Epo receptor expression in precursor cells or alternatively a reflection of an increased number of erythroid cells in C/EBP -/- livers has not been determined. Compared with wild-type animals, maturation of immature myeloid cells in vivo in response to G-CSF was not observed, as assessed by both morphology and FACS analysis of Gr-1 expression. In addition, no colony-forming units-granulocyte (CFU-G) could be obtained using C/EBP -/- newborn liver, although other types of colonies (colony-forming unit granulocyte, erythroid, monocyte, megakaryocyte [CFU-GEMM], colony-forming unit-erythroid [CFU-E], colony-forming unit-granulocyte-macrophage [CFU-GM], and colony-forming unit-macrophage [CFU-M]) were quantitatively equal to wild-type animals. These findings suggested that much of the phenotype may be due to decreased or absent G-CSF signaling due to markedly reduced receptor levels. However, G-CSF receptor knockout animals produce mature granulocytes, in contrast to C/EBP knockouts, strongly suggesting that there must be important C/EBP target genes in myeloid progenitors in addition to the G-CSF receptor.219 Transplantation of C/EBP fetal liver into sublethally irradiated animals resulted in detection of T cells but not myeloid cells of donor origin, showing that the defect is indeed in the hematopoietic cells.28
A number of studies have pointed to the role of C/EBP in myeloid cells. The avian homolog of C/EBP (NF-M) is a myeloid-specific factor that activates the promoter for cMGF, which is related to G-CSF and IL-6.196-199 In mammalian cells, C/EBP has been described as having low activity until activated by LPS, IL-1, IL-6, and other inflammatory mediators, which induce its translocation to the nucleus, where it can activate cytokine genes such as IL-6 and G-CSF.185,220 Changes in C/EBP phosphorylation (but not in C/EBP) have also been described during myeloid differentiation of a progenitor cell line.160 Human C/EBP is also known as NF-IL6.185 C/EBP can also be activated in other cell types by phosphorylation without translocation.221 In one report, targeted disruption of C/EBP leads to defects in killing of Listeria and tumor cells by macrophages.222 In a second study, disruption of C/EBP led to an increase in IL-6 production (previously it was thought that C/EBP, or NF-IL6, was essential for IL-6 production) and hyperproliferation of a number of different hematopoietic lineages, a syndrome resembling Castleman's disease.223 Knockout animals from both of these studies can get this syndrome as the animals get older, but it is not seen in young mice kept in a sterile environment.224 In these younger mice, in the absence of inflammation, myelopoiesis was apparently not adversely affected, consistent with a role of C/EBP in cytokine activation rather than lineage development.
As noted above, C/EBP (NF-IL6) regulates a number of cytokine genes and may contribute to normal myeloid development as well as activation of mature myeloid cells in response to an inflammatory stimulus. In particular, targeting of C/EBP resulted in a reduction of G-CSF production in macrophages but not other cell types.222 C/EBP has been noted to regulate the promoters for several myeloid granule proteins, including myeloperoxidase and neutrophil elastase.87,88,160 In addition, C/EBP sites, like PU.1 sites, are critical for the activity of a number of myeloid CSF receptor promoters, including the M-CSF receptor,117 the GM-CSF receptor ,54 and the G-CSF receptor promoter.53 In the C/EBP knockout mice, G-CSF receptor mRNA was selectively and significantly reduced.28 Interestingly, no reduction was noted in the levels of M-CSF receptor and GM-CSF receptor ( and chain) mRNA, suggesting that perhaps other factors (such as C/EBP) can compensate for C/EBP in some but not all instances.
With respect to the possible role of C/EBP proteins in leukemia, the C/EBP proteins have not been implicated as transforming proteins, with the exception of CHOP10.190,225 Indeed, C/EBP has been shown to inhibit cell proliferation in fibrosarcoma lines through the cyclin-dependent kinase inhibitor p21183 and can act as a tumor suppressor of hepatoma lines and other cell types.181,182 The human C/EBP gene maps to chromosome 19q13.1 and C/EBP maps to 20q13.1.226 Neither of these is a frequent site of chromosomal translocations found in human myeloid leukemia. Studies of C/EBP expression in primary human leukemias have not been reported. However, given the phenotype of the C/EBP knockout mouse, in which there appears to be a block in granulocyte maturation, it will be of interest to look for abnormalities of C/EBP expression or mutations in myeloid leukemias, which also represent states with a block in maturation.
In summary, the C/EBP proteins are differentially expressed and can form many interactions with themselves and other transcription factors. These studies show that C/EBP (and C/EBP) may be involved in activation of cytokines in mature cells, whereas C/EBP has a major role in granulocytic maturation through regulation of the G-CSF receptor and other as yet not identified target genes.
Other factors binding to CCAAT sites and myeloid development.
In addition to the C/EBP proteins, the CCAAT displacement protein (CDP) has also been implicated in myeloid development. This protein was observed to negatively regulate genes by binding to a CCAAT box and displacing the binding of positively acting factors.227 It was subsequently shown to be capable of binding to the gp91phox promoter and repressing this cytochrome component gene expressed specifically in myeloid cells.228,229 At this time no characterization of the positively acting factors that are presumed to be displaced at this site has been made. CDP is expressed at highest levels in undifferentiated myeloid cell lines and is downregulated with differentiation, providing a mechanism for the upregulation of gp91phox observed with myeloid maturation. Importantly, this is one of the few examples explaining the potential mechanism of upregulation of myeloid targets with myeloid differentiation. In most other cases, the mechanism of upregulation is largely unknown. Recently, it has been shown that CDP can also repress the lactoferrin promoter.230 In these studies, overexpression of CDP in myeloid stem cells blocked lactoferrin expression after G-CSF-induced neutrophil maturation without blocking phenotypic maturation. Furthermore, these investigators observed coordinate repression of multiple secondary granule protein genes, including lactoferrin, neutrophil collagenase, and neutrophil gelatinase, suggesting that CDP repression is a common mode of regulation of this class of myeloid promoters (N. Berliner, unpublished observations). Other factors might also act in a similar manner to repress positive activators during differentiation. For example, a factor that is downregulated during adipocyte differentiation and inhibits C/EBP function, presumably through its similarity to carboxypeptidase, has recently been described,231 but it is not known if it inhibits C/EBP in hematopoietic cells.
| |
AML1 AND THE CBF FAMILY |
An example of a transcription factor that plays an important role in normal monocytic gene expression and in acute myelogenous leukemia is AML1. AML1 is a member of the core binding factor (CBF) or polyoma enhancer binding protein 2 (PEBP2) family of transcription factors. The CBF factors consist of heterodimers between DNA binding subunits and a subunit (CBF) that does not bind DNA directly but that enhances the binding of the subunit.232,233 Multiple subunit genes, including CBFA1, AML1 (CBFA2), and CBFA3, have been detected,233-237 although the role of these other AML1 family members in myeloid development and leukemia is not clear. In addition, alternatively spliced isoforms of the and subunits have been detected. In particular, a short form and two long forms of AML1 have been described, and it is the long form that appears to include the transactivation function.235-238 All of the CBF proteins contain a runt domain, which is similar to the Drosophila pair-rule gene, runt, an early acting segmentation protein that regulates the expression of other segmentation genes.239,240 This runt homology domain (rhd) confers the ability of AML1 to bind to its consensus sequence, TGT/cGGT, and the ability of AML1 to interact with its cofactor CBF, which enhances the DNA binding ability.232,233,241
AML1, normally expressed in hematopoietic tissues and during myeloid differentiation,134,237,242 is also expressed in nervous tissue, skeletal muscle, and reproductive tissues as well.243 Knockout studies of AML1 have determined that AML1 is necessary for normal development of all hematopoietic lineages,49,50 and similar effects have been observed with targeted disruption of the CBF subunit.244 In these studies, primitive hematopoiesis was apparently normal, but severe impairment of definitive hematopoiesis was observed both in the animals and during in vitro differentiation of -/- ES cells, with defects observed in all lineages examined.
AML1 may act to facilitate the action of other adjacent transcription factors. The AML1 site in the M-CSF receptor promoter is located between the C/EBP and PU.1 sites, two transcription factors that are important for myeloid gene expression.52,215,245 Significantly, although the C/EBP site is critical for M-CSF receptor activity in transfection experiments,52 C/EBP alone does not transactivate M-CSF receptor promoter activity. The adjacent factor AML1, along with CBF, can by itself activate the M-CSF receptor promoter sixfold, but the synergistic activation by C/EBP added to AML1 and CBF is much greater (>60-fold). All C/EBP proteins share a highly similar bZIP domain,179,184 and AML1 interacts with the bZIP fragment of C/EBP, explaining why C/EBP, C/EBP, and C/EBP can all synergistically activate the M-CSF receptor promoter with AML1. The physical interaction between C/EBP and AML1 could either stabilize binding of both to the M-CSF receptor, or their interaction might provide a surface for another transcription factor to bind and activate the M-CSF receptor promoter. Other examples of interactions of AML1 and other transcription factors include synergism with Ets-1 and c-myb to activate T-cell receptor enhancers.246-249 Because Ets factors, such as PU.1, and c-myb both play an important role in myeloid development, it is likely that these interactions with AML1 will be important in myeloid gene expression as well.
AML1 can be phosphorylated at two serine residues within a proline-, serine-, and threonine-rich region in its carboxyl terminal domain after activation of the extracellular signal regulated kinase (ERK1).250 These serine residues are critical for AML1-dependent transformation of fibroblast cell lines and ERK1-dependent transactivation of a T-cell receptor enhancer target gene. IL-3 treatment of the hematopoietic cell line BaF3 results in phosphorylation of AML1, suggesting that this signalling pathway may play an important role during hematopoietic development.
Role of AML1 in leukemogenesis.
AML1 was identified by studying one of the most frequent chromosomal translocation found in AML, t(8; 21)(q22; q22).17,39,241,251,252 AML1 fusion proteins are also involved in other forms of leukemia, including t(3; 21) therapy-related acute myeloid leukemia/myelodysplasia or chronic myelogenous leukemia in blast crisis (AML1/MDS1, AML1/EAP, and AML1/Evi-1) and also the t(12; 21) in childhood B-cell acute lymphoblastic leukemias (TEL/AML1).17,172,251,253-256 The subunit of CBF, CBF, is also involved in a chromosomal inversion, inv(16)(p13; q22), associated with French-American-British (FAB) M4eo AML.257 Therefore, each of the two chains of the CBF heterodimer is directly implicated in the pathogenesis of AML.
As noted above, AML1 is involved in the (8; 21) translocation, associated with the FAB M2 form of AML, which results in the production of the AML1/ETO fusion protein. The mechanism by which AML1/ETO accomplishes leukemic transformation is unknown. In this case, the 5' part of the AML1 gene, including the amino terminal DNA binding runt domain but lacking the carboxyl terminal activation domain, is fused to almost the entire ETO gene on chromosome 8. Recent studies have indicated that this AML1/ETO fusion protein can act as a dominant negative inhibitor of AML1 transactivation of such AML1 targets as the T-cell receptor (TCR) enhancer.236,238,258 It has recently been reported that the t(12; 21) fusion protein, TEL/AML1, also causes the same interference with AML1 transactivation of the TCR enhancer.259 Therefore, the expression of some of the normal AML1 gene targets that play a key role in monocytic differentiation might be adversely affected by AML1/ETO, and these include GM-CSF,236,258 IL-3,260,261 M-CSF receptor,52 and myeloperoxidase and neutrophil elastase.87,262
Recently, it was shown that AML1/ETO and AML1 work synergistically to transactivate the M-CSF receptor promoter, thus exhibiting a different activity than previously described.263 This indicates that AML1/ETO not only can repress, but also can enhance AML1 transactivation of its target genes. Endogenous M-CSF receptor expression was examined in Kasumi-1 cells, derived from a patient with AML-M2 t(8; 21) and the promonocytic cell line, U937. Kasumi-1 cells exhibited a significantly higher level of M-CSF receptor expression than U937 cells. Bone marrow from patients with AML-M2 t(8; 21) also exhibited a higher level of expression of M-CSF receptor compared with normal controls.263 Signaling through the M-CSF receptor promotes cell proliferation by inducing the G1/S transition because of the effect on cyclins D and E.264,265 This effect on proliferation can be tied to the oncogenic nature of the M-CSF receptor, which was first discovered as the cellular counterpart to the transforming oncogene, v-fms.266 Overexpression of the M-CSF receptor causes transformation of NIH3T3 cells and in mice leads to a myeloblastic leukemia.267,268 A premature upregulation of M-CSF receptor expression by AML1/ETO could be one of the factors contributing to leukemogenesis AML.
To study how the fusion protein produced by the t(8:21) translocation leads to the development of myeloid leukemia, knock-in mice have been generated that express the AML1-ETO fusion protein. Mice heterozygous for the AML1-ETO allele die in midgestation with hemorrhaging in the central and peripheral nervous system and exhibit a severe block in fetal liver hematopoiesis.269 This phenotype is very similar to that resulting from homozygous disruption of the cbf2 (AML1) and cbf genes.49,50,244 However, significant differences between AML1-ETO knock-in and cbf2 -/- or cbf -/- mice were observed in hematopoietic CFU assays. Yolk sac from AML1-ETO knock-in mice generated solely homogenous macrophage colonies. The total number of macrophage colonies is similar to the sum of all type of colonies from yolk sacs of wild-type mice. In contrast, no colonies from cbf2 -/- or cbf -/- mice could be detected. These results, like those noted above in which the AML1-ETO fusion protein activates the M-CSF receptor promoter, indicate that the AML1-ETO fusion protein affects hematopoiesis in a manner that is not simply a block of wild-type AML1 function, and these effects could be important in leukemogenesis. Mice heterozygous for a knock-in of the cbf-myh11 allele, which mimics the inv(16)(p13; q22) associated with AML-M4Eo form of AML, also die in midgestation from the same pattern of central nervous system hemorrhaging and impairment of fetal liver hematopoiesis. However, instead of preferential macrophage differentiation from early progenitor cells, these embryos exhibit a significant delay in maturation of yolk sac-derived primitive erythrocytes.270 Although t(8:21) and inv(16) disrupt genes encoding different subunits of a single transcription factor complex, the fusion genes have different effects on hematopoiesis, consistent with their association with distinct AML subtypes.
| |
RAR: MYELOID DIFFERENTIATION AND ACUTE PROMYELOCYTIC LEUKEMIA (APL) |
Several lines of evidence indicate a key role for the retinoic acid receptor (RAR) in myeloid differentiation. Vitamin A deficiency is associated with defective hematopoiesis,271 and retinoids stimulate granulopoiesis.272,273 Retinoic acid (RA) can induce differentiation of the HL-60 cell line274 and of primary leukemic cells.275 There are three genes encoding RARs; RAR, RAR, and RAR (reviewed previously276-278 ). RAR is preferentially expressed in myeloid tissue.279-281 RAR binds to retinoic acid response elements consisting of a direct repeat (A/G)G(G/T)TCA separated by 2 or 5 nucleotides as a heterodimer with the retinoid X receptor RXR282-284 and stimulates transcription in response to all-trans retinoic acid (ATRA).285 RAR was mutated in a retinoid-resistant HL-60 cell line with this deficit corrected by re-expression of wild-type receptor.286-288 Furthermore, introduction of a dominant negative form of RAR into a multipotent hematopoietic cell line changed the fate of these cells from the granulocyte/monocyte lineage to the mast cell line.289 In addition, GM-CSF-mediated myeloid differentiation of these cells was blocked at the promyelocyte stage.45 This basic information was complimented by clinical data indicating that patients with APL could be induced into complete remission with ATRA (reviewed previously19,290 ). It was found that APL associated with t(15:17) disrupted the RAR linking it to the PML gene, yielding the fusion protein PML-RAR.291-296 PML-RAR is an aberrant retinoid receptor with altered DNA binding and transcriptional activities.292,294,296-298 PML-RAR can block the effect of wild-type retinoic acid receptor on many promoters in a dominant negative manner. Two other APL-associated rearrangements of the RAR gene were identified: translocation (11; 17)40,299 fusing the PLZF gene to RAR and t(5; 17)300 linking the nucleophosmin (NPM) gene to RAR. All three situations yield similar chimeric RAR proteins, yet only t(15; 17) patients clearly respond to ATRA therapy.301,302 Expression of the PML-RAR fusion protein in myeloid cells inhibits differentiation in the presence of low levels of ATRA303,304 and actually accelerates differentiation in the presence of pharmacologic doses of RA.304 Expression of PML-RAR in transgenic mice impairs myelopoiesis,113 and work from another group indicated that PML-RAR could induce altered myeloid development, including increased immature and mature myeloid cells, as well as a leukemic syndrome that is ATRA responsive.115 Another group has recently described similar results in PML-RAR transgenic animals using another promoter.109 Together, the experimental and clinical data indicate that RAR function is required to fully proceed through myeloid differentiation. Disruption of RAR function likely selects for the promyelocyte phenotype. However, the nature of the fusion partner and its molecular mechanisms of action apparently play a role in the ability of the leukemic cells to differentiate in response to ATRA.
ATRA treatment drives the expression of multiple myeloid genes, including those for cell surface adhesion molecules, intrinsic host defense systems, extrinsic cytokines, colony-stimulating factor receptors, structural proteins, and enzymes. Some of these are induced with some delay after ATRA treatment, making them unlikely primary targets of RAR. The few identified direct targets of RAR tend to themselves be transcription factors, including the RARs themselves.284 ATRA treatment of fresh APL cells upregulates RAR, correlating with the presence of a RARE in RAR promoter.305,306 Therefore, one way that ATRA may induce myeloid differentiation may be to upregulate the RAR gene, overcoming the dominant negative PML-RAR protein. A recently identified direct target of RAR in myeloid cells is the cyclin-dependent kinase inhibitor p21.307 Another tantalizing set of targets for RAR in myeloid differentiation includes hox family of homeobox-containing transcription factors, which are expressed in myeloid cell lines in a coordinated, dynamic manner.32,33,308-313 In embryonic carcinoma cells homozygous for a targeted disruption in the RAR gene, ATRA treatment fails to induce the hoxb1 and CRABPII expression, indicating that these are true direct targets of RAR.284,314 Identification of further direct target genes of RAR during myeloid differentiation will require use of techniques such as differential screening315 or differential display316 of myeloid cells treated for brief periods with ATRA.
Finally, although the RAR locus and all of the other nuclear receptors have been disrupted by gene targeting in mice (reviewed previously317 ), no major defects in hematopoiesis were described in these animals.318-320 This may reflect the ability of the receptors to compensate for each other in a redundant manner. This is analogous to the way alternative forms of the RAR could rescue mutated HL-60 cells with a RAR mutation.288 Multiple matings of animals deficient in the various RAR, RXR, and other nonsteroid nuclear receptors may yield further insights as to the exact requirements for this class of transcription factor in hematopoiesis.
| |
THE ZINC FINGER FAMILY AND MYELOID CELLS |
Transcription factors belonging to the zinc finger family are among the most numerous in vertebrate organisms. These proteins contain cysteine and histidine residues that coordinately bind zinc ions to form a protein loop capable of specifically interacting with DNA.321 The Drosophila Krüppel-related zinc finger proteins are distinct from other Cys/His finger proteins because they contain a relatively invariant amino acid sequence linking the zinc fingers of the form HTGEKP(F/Y)XC. This H/C link is present in a number of zinc finger transcription factor proteins of higher eukaryotes, including Sp1,322 the EGR family of transcriptional activators,323 and the WT-1 tumor suppressor protein.324,325 Myeloid-specific zinc finger proteins were identified by their similarity to the Krüppel sequence (MZF-1),30 by subtraction cloning from myeloid cells (Egr-1),25 by their involvement in chromosomal translocation involved in APL (PLZF),299,302 and by their involvement in apoptosis associated with myeloid differentiation (Requiem).326 In addition, a zinc finger gene not normally expressed in myeloid cells was isolated by its activation in murine models of leukemia by retroviral insertion (Evi-1)327 and has subsequently shown to be involved in human leukemia when fused to the AML1 gene.17,328,329 Interestingly, relatively few of these proteins were identified by traditional promoter analysis, with the notable exception of Sp1. On the contrary, these zinc finger proteins are in general factors in search of molecular targets and mechanisms in myeloid differentiation.
The PLZF gene.
The promyelocytic leukemia zinc finger (PLZF) gene, potentially important for myeloid development, was identified by its rearrangement in APL with a variant translocation t(11; 17) (q23; q21).40,299,330 The t(11; 17) APL patients were generally resistant to both chemotherapy and differentiation therapy with ATRA,302 suggesting that the nature of the fusion partner with RAR may determine the clinical course of APL. PLZF on chromosome 11 encodes a zinc finger transcription factor,299 whereas the partner protein with RAR in t(15; 17) APL is PML, a RING finger protein of unknown function (reviewed previously19 ). The t(11; 17) fusion yields two reciprocal transcripts expressed in all patients tested: PLZF-RAR, predicted to encode an aberrant retinoid receptor, and RAR-PLZF, fusing the A-activation domain of RAR to the last 7 zinc finger motifs of PLZF.
In the hematopoietic system, PLZF is expressed in myeloid but not in lymphoid cell lines.299 Upon treatment of NB4 or HL-60 cells with retinoic acid, PLZF levels decline (Chen et al299 and A. Chen, S. Waxman, and J. Licht, unpublished data). The murine homologue of PLZF was found to be expressed at highest levels in multipotent progenitor cell lines such as FDCP-MixA4 and at lower levels in committed cell lines.331 When the multipotent FDCP-MixA4 cell line was induced to differentiate, PLZF levels decreased. Murine PLZF mRNA was also detectable in pro-B-cell lines but not in more mature B- or T-cell lines.331 PLZF was not expressed in undifferentiated embryonic stem cells but was upregulated as ES cells were induced to differentiate into embryoid bodies. In the developing mouse embryo, PLZF is expressed in the aorta, gonadal, and mesonephros region (AGM), a region thought to give rise to hematopoietic stem cells. Finally, CD34+ human progenitor cells could be immunostained with PLZF antisera in a distinct nuclear speckled pattern.331 Together, this information suggests that PLZF may be a marker of and a critical gene for the early hematopoietic stem cell. Downregulation of PLZF may be a necessary step for the committed division and differentiation that accompanies normal bone marrow maturation.
By immunoprecipitation of transfected cells, the PLZF protein was identified as an 81-kD nuclear species331,332 phosphorylated on serine and threonine but not tyrosine residues (R. Shaknovich and J. Licht, manuscript in preparation). A biphenotypic T-cell/macrophage line, presumably representing a primitive transformed cell, expressed high levels of PLZF mRNA and 81-kD PLZF protein when treated with the calcium ionophore A23187, correlating with the induction of a more monocytoid phenotype. Immunofluorescent confocal microscopy showed that PLZF was localized to approximately 50 small nuclear subdomains, whereas the PML protein of t(15; 17) APL was localized in approximately 5 to 10 larger nuclear structures (nuclear bodies or PODs333-335 ) and was present before and after A23187 treatment. It is uncertain if in other cell types these two APL-associated proteins might be localized to the same nuclear domains.
PLZF is a sequence-specific DNA binding protein recognizing a sequence with a core of TAAAT.336 This site was cloned upstream of a reporter gene and was found to mediate transcriptional repression by PLZF. At least one repression domain within PLZF maps to an evolutionarily conserved sequence known as the POZ (poxvirus-zinc finger) or BTB (broad complex-tramtrack-bric-a-brac) domain.337,338 This sequence also mediates self-association by PLZF and is required for the localization of PLZF into a speckled subnuclear pattern.332,339 Whether the domains that mediate homodimerization and transcriptional repression are identical is not known. The last 7 zinc fingers of PLZF that are retained in the RAR-PLZF fusion protein can bind to the same site as the 9 zinc fingers of PLZF, suggesting that the RAR-PLZF protein could act as a dominant negative protein binding and altering transcription of PLZF target genes.
The PLZF-RAR fusion protein has properties quite similar to the PML-RAR fusion protein of t(15; 17)-associated APL. Both fusion proteins can bind as homodimers to a retinoic acid response element (RARE).297,332,339 Homodimerization by PML is mediated by a coiled-coil motif,297 whereas in PLZF the POZ domain mediates self-association.339 In an electrophoretic mobility shift assay (EMSA) both PML-RAR and PLZF-RAR homodimers are chased into novel complexes of higher and lower electrophoretic mobility by addition of RXR. This suggests that both fusion proteins may work in a similar manner, forming multimeric complexes in the cell that could act to sequester limiting amounts of RXR, the essential cofactor for RAR function, in the cell. Both PML-RAR and PLZF-RAR can act in a dominant negative manner to inhibit the activity of wild-type RAR294,296,298 and other nuclear receptors such as the vitamin D3 receptor (J. Licht and M. English, unpublished data).297 This effect can be partially relieved by overexpression of RXR, consistent with the notion that the aberrant receptors generated in APL block myeloid differentiation at least in part through limiting the ability of RAR to bind to its targets in combination with RXR. Dominant negative forms of RAR can block myeloid differentiation at the promyelocyte stage.45,289,340 This correlated with the clinical finding that RAR is rearranged in three translocations, t(15; 17), t(11; 17), and t(5; 17), all yielding APL.300,341 Thus, the block in ATRA-mediated signaling may help select the APL phenotype but may not necessarily determine whether the disease is ATRA-responsive. Further studies of the growth-inhibiting properties of PLZF suggest a reason why t(11; 17) APL may not respond to therapy.
Pools of murine myeloid 32DCL3 cells transduced with a retrovirus to overexpress the PLZF protein were significantly growth inhibited when grown in IL-3 or GM-CSF and retarded in the G1 phase of the cell cycle. In addition, the cells exhibited a higher rate of programmed cell death and a reduced ability to differentiate in response to G-CSF or GM-CSF.342 The high level of expression of PLZF in the hematopoietic precursor cell may play a role in the relative quiescence of these cells. Downregulation of PLZF during myeloid differentiation may be accompanied by cycles of committed cell division. In this way, PLZF does seem similar to PML,343-345 because both proteins can repress cell growth. However, t(11; 17) generates RAR-PLZF, a protein that can potentially interfere with the normal transcriptional functions of PLZF by binding to and dysregulating PLZF target genes. In contrast, the RAR-PML transcript is variably found in t(15; 17) APL19 and may not be able to affect the function of wild-type PML. Consistent with a central role for PLZF disruption in t(11; 17) APL phenotype, RAR-PLZF may confer accelerated growth to 32DCL3 cells. Hence, t(11; 17) may be a resistant disease due to the presence of two oncogenes working through different mechanisms, PLZF-RAR and RAR-PLZF. It remains to be determined what genes are targeted by PLZF and how these play a role in the growth and differentiation of myeloid tissue.
The myeloid zinc finger protein MZF-1.
MZF-1 has multiple (13) zinc finger domains, divided in two groups.346 The amino-terminal group has 4 fingers, and the carboxyl-terminal group has 9 fingers. There are acidic regions in the amino-terminal nonzinc finger portion of the protein that may be part of the transcriptional regulatory domain. Interestingly, there is a 24 amino acid glycine-proline-rich link between the first and second zinc finger regions. Glycine-proline-rich domains have also been implicated in transcriptional regulation in a large number of transcription factors, including Oct-3, Rex-1, and CP-1.346
By Northern analysis, MZF-1 was found to be specifically expressed in myeloid cell lines.346 By cRNA in situ hybridization of normal marrow, MZF-1 was found to be expressed in myeloid cells,347 from myeloblasts to metamyelocytes, but in no other marrow cell types, implying a role for MZF-1 in myeloid development. Using in situ chromosomal hybridization, MZF-1 was localized to human chromosome 19q13.4.346 It is the telomeric-most gene on 19q, with its promoter region being less than 10 kb from the telomeric repeats.348 The finding that MZF-1 is located at the telomere of chromosome 19q is significant because there is evidence that aging hematopoietic stem cells lose telomeric size with time.349 In addition, telomeres shorten with transformation of myelodysplasia to leukemia.350 With age, the incidence of stem cell disorders such as myelodysplasia and leukemia increases markedly. It is possible that the regulatory region of MZF-1 or the transcribed sequence is disrupted with age, which could play a role in the increased incidence of hematopoietic stem cell disorders.
The consensus DNA binding sites of MZF-1 were isolated by mobility shift selection of degenerate oligonucleotides and PCR amplification.351 The first finger domain, zinc fingers 1-4 (ZF1-4), bound to a consensus sequence of 5'-AGTGGGGA-3', whereas zinc fingers 5-13 (ZF5-13) bound to a consensus of 5'-CGGGnGAGGGGGAA-3'. These guanine-rich sites resemble NF-B binding sites. The full-length recombinant MZF-1 could bind to either sequence. Indeed, the two MZF-1 finger domains, ZF1-4 and ZF5-13, could bind to each other's consensus binding sequence. In addition, it was discovered that ZF5-13 probably needs all 9 fingers to bind to its consensus sequence. Deletion of as few as 3 fingers from either end of ZF5-13 abrogates DNA binding.351
Computer searches of data bases for promoter sequences that contained these consensus MZF-1 binding sites found several possible matches. The promoters of the myeloid genes CD34, myeloperoxidase, c-myb, and lactoferrin all contained consensus MZF-1 binding sites. An intriguing finding about MZF-1 was its bifunctional transcriptional regulatory activity. In the intracellular environment of adherent, nonhematopoietic cells it functions as a transcriptional repressor, and in hematopoietic cells it functions as an activator.352
MZF was found to repress the CD34 promoter and the c-myb promoter in nonhematopoietic cells.352,353 However, in one study using the hematopoietic cell lines K562 and Jurkat, MZF-1 activated transcription from the CD34 promoter.352 In another study, using different techniques, it was found that MZF-1 repressed the CD34 promoter in KG-1 cells.353
The presence of MZF-1 binding sites in several myeloid promoters and the explicit regulation of the CD34 promoter by MZF-1 point out that MZF-1 may have a general role in the regulation of hematopoietic gene expression. Lending evidence to the hypothesis that MZF-1 may be an important regulator of hematopoietic development are studies showing that blocking MZF-1 expression with antisense oligonucleotides inhibits granulopoiesis.347
MZF-1 can also disrupt the normal proliferative behavior of embryonic fibroblasts. When MZF-1 was retrovirally transduced and overexpressed in NIH 3T3 cells, where it is not normally expressed, it rapidly transformed those cells.354 However, two other myeloid transcriptional regulators, PU.1 and PRH, did not transform 3T3 cells when they were similarly overexpressed. In addition, forced overexpression of MZF-1 in IL-3-dependent FDCP1 or HL-60 cells decreased apoptosis induced by IL-3 withdrawal or retinoic acid, respectively.355,356 FDCP1 cells transduced with MZF-1 formed tumors in 70% of congenic hosts, whereas control cells did not. These data imply that the aberrant expression of nodal regulators of development can be neoplastic. It lends evidence for the hypothesis that malignancy represents normal development gone awry.
The MZF-1 promoter was recently isolated.357 There are MZF-1, PU.1, and retinoic acid receptor binding sites within the MZF-1 promoter.
The early response gene Egr-1.
Many groups have isolated Egr-1 (NFGI-A) as an early response gene induced by a variety of stimuli, primarily those that induce cell proliferation.358 Egr-1 was also cloned as an early response gene during TPA treatment of human myeloid cell lines and was noted to be upregulated during monocytic and not granulocytic differentiation of these bipotential lines.25 Overexpression and antisense studies implicated Egr-1 as an inducer of monocytic differentiation.25,359 An Egr-1 knockout mouse line has been made, but no abnormalities of monocytic differentiation or function were detected.360 In this mouse model, it is possible that other members of the Egr-1 family can compensate for loss of the Egr-1 gene.
The Wilms' tumor suppressor gene WT-1.
An enlarging body of literature suggests a role for the WT1 Wilms' tumor suppressor gene in normal and leukemic myeloid development. WT1 encodes a zinc finger transcription factor that binds to a GC-rich sequence similar to that of the Egr-1 protein (reviewed previously361 ).362 WT1 can both activate and repress transcription and in model systems inhibits cell growth363-365 and can induce programmed cell death.361,366 WT1 is expressed in normal bone marrow, particularly in CD34+ progenitor cells.367,368 CD43+/CD33-/lin- cells, believed to be very early progenitors, express the highest levels of WT1, whereas the CD33+ subset of CD34+ progenitors, reflecting a later point in differentiation, express 100-fold less WT1. WT1 is also expressed in the murine embryonic yolk sac and liver during definitive hematopoiesis.368 WT1 is expressed in a number of myeloid cell lines, and WT1 expression is downregulated in HL-60 and K562 cells at the posttranscriptional level during differentiation of these cell lines.369,370 Given that WT1 can compete for the binding site of Egr-1 and repress transcription and that Egr-1 is an activator that promotes monocytic differentiation,25,359 it is possible that the interplay between these two factors, which have opposing transcriptional effects, may play a role in the tight control of monocytic differentiation. The hypothesized role of WT1 in hematopoiesis must be tempered by the results of Kriedberg et al,371 who performed a targeted disruption of the WT1 gene in the mouse. These animals exhibited complete kidney and genitourinary agenesis, defects in the mesothelium, and cardiac defects, but to date have demonstrated no hematopoietic deficits (J. Kreidberg, personal communication, June 1996).
WT1 mRNA expression has been detected in up to 80% of cases of acute myelogenous leukemia.372,373 Whereas WT1 can be found in the marrow of normal subjects, expression in the peripheral blood is distinctly abnormal and a sign of the presence of leukemic cells.367 In addition, there was found to be a negative correlation between WT1 expression and prognosis.367 Reverse transcription-PCR (RT-PCR) assay for WT1 expression can detect minimal residual leukemic blast cells in leukemia patients and may be more sensitive than the detection of fusion gene products such as the PML-RAR fusion found in APL.367,374 There is an inherent paradox in these findings. WT1 is believed to be a classical tumor-suppressor gene, and yet it is expressed in high levels in actively proliferating leukemia. This expression may reflect the stage of differentiation of the malignant cells at the point of transformation. Alternatively, WT1 may have an oncogenic effect when overexpressed in hematopoietic tissue. Recent data indicate that WT1 expression may be important for leukemic cell growth. When myeloid leukemic cell lines were treated with antisense WT1 oligonucleotides, cellular proliferation was inhibited and programmed cell death was induced.375,376 In addition, fresh human leukemia sample growth was inhibited by these antisense WT1 oligonucleotides.376 Mutation of WT1 may also play a role in leukemogenesis. Initially, a mutation was detected in the remaining WT1 allele of a WAGR patient who had been previously treated for Wilms' tumor.377 This mutation affected a cysteine residue in the zinc finger region and would be predicted to abolish DNA binding by WT1. This suggested that complete loss of WT1 function in the myeloid lineage might be associated with the development of leukemia. More recent data from this same group indicate that 15% of cases of AML have point mutations of WT1.320 These were heterozygous mutations leading to the formation of truncated forms of WT1 devoid of zinc finger DNA-binding motifs. Such truncated proteins may act in a dominant negative manner to inhibit the transcriptional effects of wild-type WT1.378-380 This again suggests that WT1 may play a role in the control of leukemic cell growth.
The mechanism of action of WT1 in affecting myeloid growth is not defined, but one important candidate target gene is c-myb, which contains an Egr-1 site within its promoter. This site acts as a negative regulatory element. WT1 binds to this site in vitro and can repress the c-myb promoter.381 This is intriguing given that forced expression of c-myb blocks myeloid differentiation, and treatment of myeloid cells with antisense c-myb oligonucleotides blocks proliferation.42,382,383 WT1 could therefore affect myeloid growth indirectly through action on c-myb.
| |
HOMEOBOX PROTEINS |
The homeobox genes are a group of proteins defined by a specific helix-turn-helix DNA binding motif, the homeo domain.313,384,385 These regulators have been shown by mutational and knockout studies to play a major role in segmental development of many species, from Drosophila to mouse.308,386 The genomic organization of these genes in mammals, including humans, is arranged in four clusters that are expressed in a temporal fashion related to their physical position in the cluster. Recently, a number of exciting studies have shown that this class of proteins may indeed influence myeloid development.308,313 A number of studies have investigated the hematopoietic expression of homeobox genes, including ones expressed in stem cells.32 One of these, HoxA10, was noted to be expressed specifically in myeloid cells.309 Subsequent studies showed that HoxA10 mRNA was expressed at higher levels in human CD34+ cells than other homeobox genes and downregulated during myeloid development.32,33 Expression could not be detected in mature neutrophils and monocytes. These studies suggest that HoxA10 is upregulated and then downregulated as stem cells differentiate into mature myeloid cells.387 Interestingly, HoxA10 was detected in a variety of cases of myeloid leukemia, except for APL (M3), and decreased in lymphoid blast crisis of chronic myelogenous leukemia (CML).33 HoxA10 was localized to chromosome 7p14-21.33 Its expression was detected in several cases of monosomy 7, so complete loss of HoxA10 in this abnormality, frequently seen in AML, is not the mechanism of leukemogenesis. Although the targets of HoxA10 are not known, its function has been investigated by overexpression studies using retroviral infection of murine bone marrow.313,388 Overexpression of HoxA10 led to abnormalities of progenitor cells, with increased numbers of megakaryocytic and blast colonies in vitro and increased myeloid progenitors in vivo, but peripheral blood counts were normal. A substantial number of lethally irradiated congenic transplant recipients developed acute myelogenous leukemia, with high blast counts, 5 to 10 months posttransplantation.
In addition to overexpression studies, the function of HoxA10 has been investigated by knockout experiments. Mice with targeted disruption of HoxA10 are fully viable but have defects in both male and female fertility.389 Investigation of the hematopoietic system of these mice showed an increase in peripheral blood neutrophils and monocytes to a level twofold that of wild-type or heterozygote littermates.387 Interestingly, investigation of CFU in the knockout animals showed no change in numbers of GM, M, or GEMM colonies, but these myeloid CFU were extremely large in size, with a fivefold increase in cell number, and contained a preponderance of immature myeloblastic cells.387 In summary, these studies emphasize the role of HoxA10 in myeloid development and make it likely that HoxA10 plays a critical role in control of proliferation at the myeloblastic or promyelocytic stage. Recently, the effects of targeted disruption of the HoxA9 gene have been described.390 HoxA9 is expressed at high levels in human CD34+ cells and myeloid progenitors, but at lower levels in CD34- cells. It is also expressed in lymphocytes. Disruption of HoxA9 resulted in a 30% to 40% reduction in lymphocytes and granulocytes and a blunted response to G-CSF, suggesting a role for HoxA9 at the level of committed progenitors.390
A number of other homeobox genes have been studied by overexpression and antisense studies, and many of these are of direct relevance to myeloid development. Several of these studies, like those of HoxA10, suggest that downregulation of homeobox genes in progenitors may be important for myeloid maturation. Overexpression of HoxB8, when combined with high levels of IL-3, can induce myeloid leukemia in mice.391 These studies suggested that two events were necessary for leukemogenesis: an increase in progenitor proliferation, mediated by IL-3, and a block in myeloid differentiation, mediated by increased HoxB8 expression.392 Consistent with the notion that downregulation of homeobox genes may be necessary for proper differentiation, antisense studies directed at a diverged homeobox gene expressed in CD34+ cells, HB24, was shown to block IL-3- and GM-CSF-induced proliferation, and overexpression inhibited differentiation. Interestingly, increased expression of HB24 was seen in some cases of AML.393 Another negative regulator of myeloid gene expression that is downregulated with myeloid differentiation, the CDP protein discussed above, is a homeobox protein.229 The HoxB6 gene is expressed in erythroid cells, and blocking its expression with antisense oligonucleotides can induce myeloid differentiation of erythroid lines.312 These studies suggest that HoxB6, like GATA-1, may serve as a switch to direct multipotential progenitors from the myeloid to the erythroid lineage (see discussion below).
In contrast to the studies cited above, in which the homeobox is either downregulated in mature myeloid cells or expressed in other lineages, several studies have looked at homeobox genes expressed in mature myeloid cells. Hlx is expressed in macrophages and neutrophils, and overexpression using a retroviral construct induces myeloid maturation.394 HoxB7 was shown to be induced during vitamin D3 monocytic differentiation of promyelocytic HL-60 cells.395 Overexpression of HoxB7 inhibited neutrophilic differentiation of HL-60 cells, and antisense inhibited GM-CFU.395 PRH (HEX) is an orphan homeobox gene initially identified by three groups using PCR with degenerate primers to conserved homeodomain sequences.359,396,397 PRH is located on human chromosome 10, where HOX 11 is also located.396 PRH is downregulated by TPA-induced monocytic differentiation, but not by retinoic acid-induced granulocytic differentiation.398 PRH is not oncogenic when transduced into 3T3 cells.354
Finally, regulators of homeobox genes may play important roles in myeloid development and leukemia. The MLL (Hrx) gene, a regulator of homeobox genes,399 is implicated in mixed lineage (lymphoid/myeloid) leukemia.399-401 Another modulator of homeobox function is the Pbx1 gene.402 A fusion protein formed between E2A and Pbx contributes to the t(1:19) pre-B-cell ALL, but expression of the E2A-Pbx fusion protein in mice induces myeloid leukemia.403 Pbx1 binds cooperatively to HoxB4, B6, and B7, all of which have been implicated in myeloid development, as described above, but not to HoxA10.402 In summary, there are many studies implicating homeobox genes in normal myeloid development and leukemia, and the next several years should lead to exciting new developments.
| |
OTHER FACTORS INVOLVED WITH MYELOID DEVELOPMENT AND/OR LEUKEMIA |
A number of other transcription factors have been implicated in myeloid development or leukemia. Because of space limitations, they shall only be briefly mentioned.
c-myb.
Myb was first isolated as a retroviral oncogene and as an Ets fusion protein can transform chicken hematopoietic cells, resulting in a variety of different leukemias.12a,404,405 C-myb is a sequence-specific transcription activator.406 In hematopoietic cells, it is expressed in proliferating progenitors and downregulated with differentiation, with a preferred if not specific expression pattern in myeloid cells.42 This downregulation is important for differentiation of myeloid cell lines.382,383 Knockout of the c-myb gene results in embryonic lethality with a failure of hematopoiesis of fetal liver,29 and c-myb has been shown to be capable of transactivating the CD34 gene in cotransfection studies.407 However, deletion of the c-myb binding sites does not result in significant loss of human CD34 promoter activity,408 and murine CD34 is reportedly expressed at normal levels in c-myb knockout mice,409 so the mechanism by which c-myb regulates CD34 is unclear at this time. Recently, c-myb has been shown to regulate the CD13 gene in myeloid cells410 and downregulate the M-CSF receptor.164 Finally, myb can interact with the AML1 family of transcription factors247 and can synergize with C/EBP to transactivate a myeloid promoter, neutrophil elastase.88 Myb can also cooperate with C/EBP factors to activate target genes in myeloid cells, possibly mediated through the p300/CBP coactivator.197,411,412 All of these results point to an important role of c-myb in myeloid development. In addition, c-myb has been reported to regulate c-myc expression,413 and some of its effects on myeloid development could be mediated through this mechanism (see below).
c-myc.
C-myc was isolated as an oncogene whose dysregulation plays a role in avian and human lymphomas. It is a sequence-specific transcription factor and implicated in many processes involving tumorigenesis and apoptosis.12a,373,414,415 Of specific relevance to this review are early studies showing that myc is downregulated in myeloid cell lines as they are induced to differentiate and that treatment of these lines with antisense oligos induces myeloid differentiation.41 Activation of an inducible myc-estrogen receptor construct in a myeloid line can block differentiation.416 Another aspect of c-myc that may be important in myeloid differentiation is that it has been shown to heterodimerize with a number of partners. Dimerization with max leads to transcriptional activation, and dimerization with mad leads to loss of transcriptional activity. It has been shown that mad can be induced with maturation of myeloid cell lines, consistent with the loss of proliferation in these cells.417,418 Finally, a third interesting aspect of myc is that it has been shown to repress the C/EBP promoter in adipocytes.193 C/EBP expression increases with adipocyte differentiation as c-myc decreases, and blocking myc function can increase C/EBP expression and differentiation. Whether c-myc plays a similar role in myeloid expression of C/EBP is not clear at this time.
NF-B and rel proteins.
In addition to being a major regulator of lymphoid activation, NF-B has been shown to be activated in myeloid cell lines induced toward monocytic differentiation with TPA. It is thought that this activation may play an important role in human immunodeficiency virus (HIV) replication and production of cytokines, such as macrophage inflammatory protein-1.419,420 The NF-B and related rel proteins can interact with C/EBP proteins and as such may modulate the role of C/EBP factors in myeloid cells.210,211,421 Targeted disruption of the relB gene leads to myeloid hyperplasia, suggesting a role for this family in myeloid development.422
Mixed lineage leukemia (MLL) protein.
The MLL protein (also known as Hrx or All-1) has been shown to be involved in translocations of 11q23 associated with mixed (myeloid and lymphoid) leukemia.12a,399-401,423,424 MLL is a very large transcription factor with a number of different motifs, including a SET domain found in the trithorax and polycomb genes, which regulate homeobox gene expression in Drosophila. MLL has activation and repression domains, and the translocations of the MLL gene suggest that loss of the activation and retention of the repression domains could alter the expression of as yet unidentified target genes as a mechanism of leukemogenesis.425 The knockout of the MLL gene caused altered Hox expression and segmental identity, with myeloid defects in heterozygote animals.399 In addition, MLL or All-1 -/- ES cell show a block in maturation during CFU formation in vitro, suggesting that normal function of this gene is important for hematopoietic differentiation.426
p53.
The p53 protein is a tumor-suppressor gene involved in many types of cancer and thought to play a normal role in elimination of cells that have damaged genomes. p53 has been showed to be mutated in many types of human leukemia, including myeloid leukemias.427,428 Other studies have implicated mutations of p53 in CML, particularly in blast crisis.429 p53 has also been shown to be a sequence specific transcriptional activator that can activate target genes, such as the cyclins.430 Wild-type p53 has been shown to induce differentiation of myeloid cell lines.431 Therefore, it is likely that loss of p53 function plays an important role in leukemogenesis.
c-Jun.
The c-jun proto-oncogene forms a heterodimer with c-fos to form the AP-1 transcription factor, which has been shown to be involved in cell proliferation and activation.432 C-jun is an early response gene in differentiating myeloid cells, and its expression is upregulated in myeloid cell lines during differentiation.433,434 One known myeloid target is the macrophage scavenger receptor.166 AP-1 is antagonized by the retinoic acid receptor,435 but the PML/RAR fusion protein found in APL is an activator of c-jun, and this may contribute to the proliferative status of the leukemic cells.436 C-jun can also physically interact with PU.1151; this interaction may be important during myeloid differentiation.
| |
MODELS OF HOW MYELOID TRANSCRIPTION FACTORS WORK ON PROMOTERS TO DIRECT MYELOID DIFFERENTIATION |
The study of myeloid promoter elements has suggested several models of how myeloid genes are regulated. In addition, these studies suggest a model of how myeloid differentiation might be directed by transcription factors in normal cells and how abnormal function of transcription factors may play a role in leukemia. There is a strikingly similar promoter geography of three myeloid CSF receptor promoters, all of which use C/EBP and PU.1 sites (Fig 2). There is likely significant redundancy of some CSF pathways, in that different myeloid CSFs can direct myeloid CFU formation in vitro and that knockout studies of some CSFs, such as GM-CSF, did not show significant hematopoietic abnormalities. However, single transcription factors, such as C/EBP and/or PU.1, could affect the myeloid lineage by regulating expression of multiple CSF receptors. Alternatively, a factor such as AML1, which is expressed at high levels in T cells in addition to myeloid cells,437 could possibly regulate not only myeloid CSF receptors, such as the M-CSF receptor, but also CSFs produced in T cells that bind to those receptors, such as GM-CSF258 and IL-3.260
View larger version (13K):
[in this window]
[in a new window]
| Fig 2.
Structure of the human myeloid CSF receptor promoters. As with many myeloid promoters, relatively small regions direct activity and specificity in transient transfection studies; in addition, there is no well-defined TATA box. The major transcription start site is designated by the horizontal arrow. Shown are the locations of binding sites for PU.1, C/EBP, and AML1. The PU.1 site in the G-CSF receptor promoter is located in the 5' untranslated region, at bp +3653; a functional PU.1 site is also found in the 5' UT region of the PU.1 promoter.55 In unstimulated myeloid cell lines, the major C/EBP gene product is C/EBP.53,54,215 In newborn livers from C/EBP -/- animals, only expression of the G-CSF receptor is significantly reduced.28 In PU.1 -/- animals and ES cells, expression of the M-CSF receptor is significantly reduced or undetectable.162,163
|
|
The M-CSF receptor promoter itself is a good example of how combinations of factors, not exclusively myeloid-specific, can act together to generate a myeloid-specific promoter (Fig 1). In the case of the M-CSF receptor promoter, there are adjacent binding sites for PU.1,117 which is expressed in myeloid and B cells95,124; AML1, expressed in all white blood cells234,437; and C/EBP, expressed in myeloid cells and not lymphocytic cells.52,195,199 The common cell type in which all three of these factors are expressed is myeloid and not lymphocytic cells. In addition to a shared specificity of expression in myeloid cells, AML1 and C/EBP215 can interact physically in a specific manner and can synergize to activate the M-CSF receptor.215 C/EBP and PU.1 can also physically interact in a specific way.88,142 Therefore, the combinatorial effect of these factors is enhanced.
The findings described in this review of how these transcription factors function suggest a model of how they may direct myeloid development. This model suggests that the apparently irreversible pattern of hematopoietic lineage development may proceed in three steps (Fig 3). (1) In stem cells or more likely early multipotential progenitors, processes that are not defined yet result in the activation of a specific transcription factor, such as GATA-1 or PU.1. (2) Increased activation of expression and/or function of this factor leads to increased expression of a specific growth factor receptor and at the same time through an autoregulatory mechanism increases expression of the specific transcription factor. (3) Further differentiation is mediated by the influence of the specific growth factor, augmented by the upregulation or downregulation of other differentiation genes regulated by the transcription factor.
View larger version (22K):
[in this window]
[in a new window]
| Fig 3.
Model of induction of hematopoietic differentiation by specific transcription factors. In this model, transcription factors are expressed at low levels in CD34+ stem cells,134 as are specific growth factor receptors. Under direction of signals that are as yet not defined, such as the influence of stromal interactions or growth factor signalling, specific transcription factors, such as GATA-1 or PU.1,44 are upregulated. Upregulation of specific transcription factors leads to their autoregulation and upregulation of specific growth factor receptors, resulting in increases in proliferation, differentiation, and suppression of apoptosis of specific lineages. Downregulation of specific factors (such as GATA-1 during myeloid development) may also play an important role.
|
|
Both GATA-1 and PU.1 activate important growth factor receptors for the erythroid and myeloid lineages, respectively. For example, during erythroid development from multipotential progenitors, GATA-1 is activated (and PU.1 is repressed).44,438 Previous studies have shown that GATA-1, which plays a key role in erythroid development,5 can transactivate its own promoter.439 Among its many gene targets, GATA-1 can stimulate expression of the erythropoietin receptor.440 It is possible that GATA-1 activation initiates an irreversible differentiation process in which GATA-1 stimulates its own expression and that of the erythropoietin receptor, allowing that progenitor to proliferate and survive in the presence of erythropoietin.
Conversely, activation of PU.1 (and repression of GATA-144,438 ) in a progenitor may lead to stimulation of PU.1 expression through an autoregulatory loop,55 as well as the M-CSF receptor,117 allowing that progenitor to proceed along the path of myeloid development. This model would also suggest that downregulation of GATA-1 during myeloid differentiation and of PU.1 during erythroid commitment might also be important. Consistent with this concept are results suggesting that overexpression of GATA-1 in multipotential cell lines result in a block of myeloid differentiation81,441 and the finding that overexpression of PU.1 due to Friend virus insertion near the Spi-1 locus in early erythroblasts leads to a block in erythroid differentiation and murine erythroleukemia.37,38,125,126 A final addition to this model would be findings showing that GATA-1 and PU.1 could downregulate each other. Although there is a GA-rich sequence in the proximal GATA-1 promoter, PU.1 reportedly does not bind to this region.439 There is a site in the proximal PU.1 promoter that binds to GATA-1 and GATA-2, and coexpression of either GATA protein results in a twofold repression in PU.1 expression in myeloid and nonmyeloid lines.55 The role of this site in downregulation of PU.1 in early myeloid cells remains to be determined. Finally, this model is consistent with findings indicating that GATA-1 does not play a major role in myeloid development5 and that GATA-2 is either not expressed in or downregulated in myeloid cells.78 Other myeloid promoters, such as CD11b,76 also have sites in their promoters that bind GATA-1 and GATA-2, but are not functional as assessed either by transient analysis of specific point mutations or by transactivation studies.116
Recent findings suggest that C/EBP factors, notably C/EBP, may also contribute to myeloid development using mechanisms similar to the model invoking GATA and PU.1. It is not yet known how C/EBP proteins are regulated during multilineage development of CD34+ cells, but it does appear to be selectively expressed at high levels in neutrophilic and not monocytic or erythroid cells (H.S. Radomska and D.G. Tenen, manuscript submitted). If it is upregulated selectively during neutrophilic development, it may also be autoregulated in these cells as it is in adipocytes.192,194 It is known to augment expression of the G-CSF receptor promoter53 and by this mechanism could promote the development of neutrophilic cells in a manner similar to that described above for PU.1 and GATA-1 for the monocytic and erythroid lineages, respectively.
| |
QUESTIONS FOR THE FUTURE |
In this review, we have attempted to summarize what is known about myeloid transcription factors, lineage development, and differentiation. Clearly many advances have been made in the last few years, but many very important questions remain unanswered.
How do the combinations of these myeloid transcription factors make a specific lineage? Although we have provided some concepts based on studies of the M-CSF receptor, clearly other genes are regulated by other combinations of factors.
What differences among myeloid subtypes (monocytes, neutrophils, and eosinophils) are determined by transcription factors? An example is the role of C/EBP in neutrophilic development.
How are the regulators (PU.1, C/EBP, etc) themselves regulated in stem cells and multipotential progenitors? Are they activated by cytokines or other extrinsic signals, or is the process stochastic and autoregulatory? Are they in turn regulated by other regulators, such as homeobox genes?
Are there truly myeloid locus control regions, scaffold and matrix attachment regions, and other elements that are important for expression of myeloid genes in the proper chromosomal context?
What are the negative regulatory loops? Do repressors like CDP228 or AEBP1231 play a role? What is the role of GATA-1?
Why is it that factors expressed in other lineages (such as PU.1 in B cells) do not induce expression of myeloid genes in those lineages? Is it because combinatorial effects of factors are needed for myeloid expression or because of negative regulation in nonmyeloid cells?
What is the role of myeloid transcription factors in apoptosis? Do they promote myeloid development by inhibition of apoptosis?
How does signalling affect myeloid development? What is the role of Janus kinases (JAKs) and STATs?13,442,443 To date, knockout studies have not shown these factors to be essential for myeloid development. What is the role of hematopoietic cell phosphatase, whose mutation results in increased macrophage production?444,445 What is the role of NF1?446,447
What are the mechanisms of leukemic development? The studies summarized in this review, in which we have characterized targets of myeloid transcription factors and models of how they could induce myeloid development, suggest a number of mechanisms in which abnormalities of myeloid transcription factor function could play a role in myeloid leukemias, which represent a block in early myeloid differentiation. Translating the knowledge of what we understand about myeloid gene regulation to understanding the pathogenesis of leukemia and perhaps developing new therapies will be the major challenge for future studies.
| |
FOOTNOTES |
Submitted November 15, 1996;
accepted February 7, 1997.
Supported by National Institutes of Health Grants No. CA41456 and DK48660 (to D.G.T.), HL48914 (to R.H.), CA59936 (to. J.D.L.), and CA59589 (to D.-E.Z.) and by American Cancer Society Grants No. DHP-160 (to J.D.L.) and DHP-166 (to D.-E.Z.). R.H. and J.D.L. are Scholars of the Leukemia Society of America.
Address reprint requests to Daniel G. Tenen, MD, Harvard Institutes of Medicine, Room 954, 77 Avenue Louis Pasteur, Boston, MA 02115.
| |
ACKNOWLEDGMENT |
The authors apologize in advance to the many investigators whose work we were unable to cite due to space limitations. We also thank David Hume, Hanna Radomska, Laura Smith, Milton Datta, and Gerhard Behre for their careful reading of the manuscript and thoughtful suggestions and Jim Griffin for his patience.
| |
REFERENCES |
1.
Davis RL,
Weintraub H,
Lassar AB:
Expression of a single transfected cDNA converts fibroblasts to myoblasts.
Cell
51:987,
1987[Medline]
[Order article via Infotrieve]
2.
Blau HM,
Baltimore D:
Differentiation requires continuous regulation.
J Cell Biol
112:781,
1991[Free Full Text]
3.
Shivdasani RA,
Orkin SH:
The transcriptional control of hematopoiesis.
Blood
87:4025,
1996[Free Full Text]
4.
Orkin SH:
Transcription factors and hematopoietic development.
J Biol Chem
270:4955,
1995[Free Full Text]
5.
Pevny L,
Simon MC,
Robertson E,
Klein WH,
Tsai SF,
D'Agati V,
Orkin SH,
Costantini F:
Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1.
Nature
349:257,
1991[Medline]
[Order article via Infotrieve]
6.
Warren AJ,
Colledge WH,
Carlton MB,
Evans MJ,
Smith AJ,
Rabbitts TH:
The oncogenic cysteine-rich LIM domain protein rbtn2 is essential for erythroid development.
Cell
78:45,
1994[Medline]
[Order article via Infotrieve]
7.
Shivdasani RA,
Mayer EL,
Orkin SH:
Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL.
Nature
373:432,
1995[Medline]
[Order article via Infotrieve]
8.
Georgopoulos K,
Bigby M,
Wang JH,
Molnar A,
Wu P,
Winandy S,
Sharpe A:
The Ikaros gene is required for the development of all lymphoid lineages.
Cell
79:143,
1994[Medline]
[Order article via Infotrieve]
9.
Urbanek P,
Wang ZQ,
Fetka I,
Wagner EF,
Busslinger M:
Complete block of early B cell differentiation and altered patterning of the posterior midbrain in mice lacking Pax5/BSAP.
Cell
79:901,
1994[Medline]
[Order article via Infotrieve]
10.
Lubbert M,
Herrmann F,
Koeffler HP:
Expression and regulation of myeloid-specific genes in normal and leukemic myeloid cells.
Blood
77:909,
1991[Free Full Text]
11.
Nichols J,
Nimer SD:
Transcription factors, translocations, and leukemia.
Blood
80:2953,
1992[Abstract/Free Full Text]
12.
Rabbitts TH:
Chromosomal translocations in human cancer.
Nature
372:143,
1994[Medline]
[Order article via Infotrieve]
12a. Wolff L: Contribution of oncogenes and tumor suppressor genes to myeloid leukemia. Biochim Biophys Acta 1332:F67, 1997
13.
Darnell JE,
Kerr IM,
Stark GR:
Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins.
Science
264:1415,
1994[Abstract/Free Full Text]
14.
Moreau-Gachelin F:
Spi-1/PU.1: An oncogene of the ets family.
Biochim Biophys Acta
1198:149,
1994[Medline]
[Order article via Infotrieve]
15.
Kehrl JH:
Hematopoietic lineage commitment: Role of transcription factors.
Stem Cells
13:223,
1995[Medline]
[Order article via Infotrieve]
16.
Shapiro LH,
Look AT:
Transcriptional regulation in myeloid cell differentation.
Curr Opin Hematol
2:3,
1995[Medline]
[Order article via Infotrieve]
17.
Nucifora G,
Rowley JD:
AML1 and the 8; 21 and 3; 21 translocations in acute and chronic myeloid leukemia.
Blood
86:1,
1995[Free Full Text]
18.
Hagman J,
Grosschedl R:
Regulation of gene expression at early stages of B-cell differentiation.
Curr Opin Immunol
6:222,
1994[Medline]
[Order article via Infotrieve]
19.
Grignani F,
Fagioli M,
Alcalay M,
Longo L,
Pandolfi PP,
Donti E,
Biondi A,
LoCoco F,
Pelicci PG:
Acute promyelocytic leukemia  From genetics to treatment.
Blood
83:10,
1994[Free Full Text]
20.
Metcalf D:
Hematopoietic regulators Redundancy or subtlety.
Blood
82:3515,
1993[Free Full Text]
21.
Roberts R,
Gallagher J,
Spooncer E,
Allen TD,
Bloomfield F,
Dexter TM:
Heparan sulphate bound growth factors: a mechanism for stromal cell mediated haemopoiesis.
Nature
332:376,
1988[Medline]
[Order article via Infotrieve]
22.
Fairbairn LJ,
Cowling GJ,
Reipert BM,
Dexter TM:
Suppression of apoptosis allows differentiation and development of a multipotent hemopoietic cell line in the absence of added growth factors.
Cell
74:823,
1993[Medline]
[Order article via Infotrieve]
23.
Just U,
Friel J,
Heberlein C,
Tamura T,
Baccarini M,
Tessmer U,
Klinger K,
Ostertag W:
Upregulation of lineage specific receptors and ligands in multipotential prognitor cells is part of an endogenous program of differentiation.
Growth Factors
9:291,
1993[Medline]
[Order article via Infotrieve]
24.
Pedersen-Bjergaard J,
Rowley JD:
The balanced and the unbalanced chromosome aberrations of acute myeloid leukemia may develop in different ways and may contribute differently to malignant transformation.
Blood
83:2780,
1994[Abstract/Free Full Text]
25.
Nguyen HQ,
Hoffman-Liebermann B,
Liebermann DA:
The zinc finger transcription factor Egr-1 is essential for and restricts differentiation along the macrophage lineage.
Cell
72:197,
1993[Medline]
[Order article via Infotrieve]
26.
Scott EW,
Simon MC,
Anastai J,
Singh H:
The transcription factor PU.1 is required for the development of multiple hematopoietic lineages.
Science
265:1573,
1994[Abstract/Free Full Text]
27. Torbett BE, McKercher SC, Anderson KL, Vestal DJ, Henkel G, Maki RA: The disruption of the gene for the transcription factor PU.1 leads to multiple hematopoietic defects. Blood 86:251a, 1995 (abstr, suppl 1)
28.
Zhang D-E,
Zhang P,
Wang ND,
Hetherington CJ,
Darlington GJ,
Tenen DG:
Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein -deficient mice.
Proc Natl Acad Sci USA
94:569,
1997[Abstract/Free Full Text]
29.
Mucenski ML,
McLain K,
Kier AB,
Swerdlow SH,
Schreiner CM,
Miller TA,
Pietryga DW,
Scott WJ Jr,
Potter SS:
A functional c-myb gene is required for normal murine fetal hepatic hematopoiesis.
Cell
65:677,
1991[Medline]
[Order article via Infotrieve]
30.
Hromas R,
Collins SJ,
Hickstein D,
Raskind W,
Deaven LL,
O'Hara P,
Hagen FS,
Kaushansky K:
A retinoic acid-responsive human zinc finger gene, MZF-1, preferentially expressed in myeloid cells.
J Biol Chem
266:14183,
1991[Abstract/Free Full Text]
31.
Giampaolo A,
Sterpetti P,
Bulgarini D,
Samoggia P,
Pelosi E,
Valtieri M,
Peschle C:
Key functional role and lineage-specific expression of selected HOXB genes in purified hematopoietic progenitor differentiation.
Blood
84:3637,
1994[Abstract/Free Full Text]
32.
Sauvageau G,
Lansdorp PM,
Eaves CJ,
Hogge DE,
Dragowska WH,
Reid DS,
Largman C,
Lawrence HJ,
Humphries RK:
Differential expression of homeobox genes in functionally distinct CD34(+) subpopulations of human bone marrow cells.
Proc Natl Acad Sci USA
91:12223,
1994[Abstract/Free Full Text]
33.
Lawrence HJ,
Sauvageau G,
Ahmadi N,
Lopez AR,
LeBeau MM,
Link M,
Humphries K,
Largman C:
Stage- and lineage-specific expression of the HOXA10 homeobox gene in normal and leukemic hematopoietic cells.
Exp Hematol
23:1160,
1995[Medline]
[Order article via Infotrieve]
34.
Coppola JA,
Cole MD:
Constitutive c-myc oncogene expression blocks mouse erythroleukaemia cell differentiation but not commitment.
Nature
320:760,
1986[Medline]
[Order article via Infotrieve]
35.
Adams JM,
Cory S:
Transgenic models of tumor development.
Science
254:1161,
1991[Abstract/Free Full Text]
36.
Kreider BL,
Benezra R,
Rovera G,
Kadesch T:
Inhibition of myeloid differentiation by the helix-loop-helix protein Id.
Science
255:1700,
1992[Abstract/Free Full Text]
37.
Moreau-Gachelin F,
Tavitian A,
Tambourin P:
Spi-1 is a putative oncogene in virally induced murine erythroleukaemias.
Nature
331:277,
1988[Medline]
[Order article via Infotrieve]
38.
Paul R,
Schuetze S,
Kozak SL,
Kozak CA,
Kabat D:
The Sfpi-1 proviral integration site of Friend erythroleukemia encodes the ets-related transcription factor Pu.1.
J Virol
65:464,
1991[Abstract/Free Full Text]
39.
Miyoshi H,
Shimizu K,
Kozu T,
Maseki N,
Kaneko Y,
Ohki M:
t(8; 21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1.
Proc Natl Acad Sci USA
88:10431,
1991[Abstract/Free Full Text]
40.
Chen SJ,
Zelent A,
Tong JH,
Yu HQ,
Wang ZY,
Derre J,
Berger R,
Waxman S,
Chen Z:
Rearrangements of the retinoic acid receptor-alpha and promyelocytic leukemia zinc finger genes resulting from t(11-17)(q23-q21) in a patient with acute promyelocytic leukemia.
J Clin Invest
91:2260,
1993
41.
Holt JT,
Redner RL,
Nienhuis AW:
An oligomer complementary to c-myc mRNA inhibits proliferation of HL-60 promyelocytic cells and induces differentiation.
Mol Cell Biol
8:963,
1988[Abstract/Free Full Text]
42.
Gewirtz AM,
Calabretta B:
A c-myb antisense oligodeoxynucleotide inhibits normal human hematopoiesis in vitro.
Science
242:1303,
1988[Abstract/Free Full Text]
43.
Bavisotto L,
Kaushansky K,
Lin N,
Hromas R:
Antisense oligonucleotides from the stage-specific myeloid zinc finger gene MZF-1 inhibit granulopoiesis in vitro.
J Exp Med
174:1097,
1991[Abstract/Free Full Text]
44.
Voso MT,
Burn TC,
Wulf G,
Lim B,
Leone G,
Tenen DG:
Inhibition of hematopoiesis by competitive binding of the transcription factor PU.1.
Proc Natl Acad Sci USA
91:7932,
1994[Abstract/Free Full Text]
45.
Tsai S,
Collins SJ:
A dominant negative retinoic acid receptor blocks neutrophil differentiation at the promyelocyte stage.
Proc Natl Acad Sci USA
90:7153,
1993[Abstract/Free Full Text]
46.
Shin MK,
Koshland ME:
Ets-related protein PU.1 regulates expression of the immunoglobulin J-chain gene through a novel Ets-binding element.
Genes Dev
7:2006,
1993[Abstract/Free Full Text]
47.
Kominato Y,
Galson DL,
Waterman WR,
Webb AC,
Auron PE:
Monocyte-specific expression of the human prointerleukin 1 gene (IL1) is dependent upon promoter sequences which bind the hematopoietic transcription factor Spi-1/PU.1.
Mol Cell Biol
15:58,
1995
48.
Tsai FY,
Keller G,
Kuo FC,
Weiss M,
Chen J,
Rosenblatt M,
Alt FW,
Orkin SH:
An early haematopoietic defect in mice lacking the transcription factor GATA-2.
Nature
371:221,
1994[Medline]
[Order article via Infotrieve]
49.
Okuda T,
van Deursen J,
Hiebert SW,
Grosveld G,
Downing JR:
AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis.
Cell
84:321,
1996[Medline]
[Order article via Infotrieve]
50.
Wang Q,
Stacy T,
Binder M,
Marin-Padilla M,
Sharpe AH,
Speck NA:
Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoesis.
Proc Natl Acad Sci USA
93:3444,
1996[Abstract/Free Full Text]
51.
Maniatis T,
Goodbourn S,
Fischer JA:
Regulation of inducible and tissue-specific gene expression.
Science
236:1237,
1987[Abstract/Free Full Text]
52.
Zhang D-E,
Fujioka KI,
Hetherington CJ,
Shapiro LH,
Chen HM,
Look AT,
Tenen DG:
Identification of a region which directs monocytic activity of the colony-stimulating factor 1 (macrophage colony-stimulating factor) receptor promoter and binds PEBP2/CBF (AML1).
Mol Cell Biol
14:8085,
1994[Abstract/Free Full Text]
53.
Smith LT,
Hohaus S,
Gonzalez DA,
Dziennis SE,
Tenen DG:
PU.1 (Spi-1) and C/EBP regulate the granulocyte colony-stimulating factor receptor promoter in myeloid cells.
Blood
88:1234,
1996[Abstract/Free Full Text]
54.
Hohaus S,
Petrovick MS,
Voso MT,
Sun Z,
Zhang D-E,
Tenen DG:
PU.1 (Spi-1) and C/EBP regulate the expression of the granulocyte-macrophage colony-stimuating factor receptor gene.
Mol Cell Biol
15:5830,
1995[Abstract]
55.
Chen HM,
Ray-Gallet D,
Zhang P,
Hetherington CJ,
Gonzalez DA,
Zhang D-E,
Moreau-Gachelin F,
Tenen DG:
PU.1 (Spi-1) autoregulates its expression in myeloid cells.
Oncogene
11:1549,
1995[Medline]
[Order article via Infotrieve]
56.
Kistler B,
Pfisterer P,
Wirth T:
Lymphoid- and myeloid-specific activity of the PU.1 promoter is determined by the combinatorial action of octamer and ets transcription factors.
Oncogene
11:1095,
1995[Medline]
[Order article via Infotrieve]
57.
Hagemeier C,
Bannister AJ,
Cook A,
Kouzarides T:
The activation domain of transcription factor PU.1 binds the retinoblastoma (RB) protein and the transcription factor TFIID in vitro: RB shows sequence similarity to TFIID and TFIIB.
Proc Natl Acad Sci USA
90:1580,
1993[Abstract/Free Full Text]
58.
Eichbaum QG,
Iyer R,
Raveh DP,
Mathieu C,
Ezekowitz AB:
Restriction of interferon gamma responsiveness and basal expression of the myeloid human FcgammaR1b gene is mediated by a functional PU.1 site and a transcription initiator consensus.
J Exp Med
179:1985,
1994[Abstract/Free Full Text]
59.
Emili A,
Greenblatt J,
Ingles CJ:
Species-specific interaction of the glutamine-rich activation domains of Sp1 with the TATA box-binding protein.
Mol Cell Biol
14:1582,
1994[Abstract/Free Full Text]
60.
Zwilling S,
Annweiler A,
Wirth T:
The POU domains of the Oct1 and Oct2 transcription factors mediate specific interaction with TBP.
Nucleic Acids Res
22:1655,
1994[Abstract/Free Full Text]
61.
Nerlov C,
Ziff EB:
CCAAT/enhancer binding protein-alpha amino acid motifs with dual TBP and TFIIB binding ability co-operate to activate transcription in both yeast and mammalian cells.
EMBO J
14:4318,
1995[Medline]
[Order article via Infotrieve]
62.
Roberts WM,
Shapiro LH,
Ashmun RA,
Look AT:
Transcription of the human colony-stimulating factor-1 receptor gene is regulated by separate tissue-specific promoters.
Blood
79:586,
1992[Abstract/Free Full Text]
63.
Fleming JC,
Pahl HL,
Gonzalez DA,
Smith TF,
Tenen DG:
Structural analysis of the CD11b gene and phylogenetic analysis of the alpha-integrin gene family demonstrate remarkable conservation of genomic organization and suggest early diversification during evolution.
J Immunol
150:480,
1993[Abstract]
64.
Seto Y,
Fukunaga R,
Nagata S:
Chromosomal gene organization of the human granulocyte colony-stimulating factor receptor.
J Immunol
148:259,
1992[Abstract]
65.
Chen HM,
Pahl HL,
Scheibe RJ,
Zhang D-E,
Tenen DG:
The Sp1 transcription factor binds the CD11b promoter specifically in myeloid cells in vivo and is essential for myeloid-specific promoter activity.
J Biol Chem
268:8230,
1993[Abstract/Free Full Text]
66.
Zhang D-E,
Hetherington CJ,
Tan S,
Dziennis SE,
Gonzalez DA,
Chen HM,
Tenen DG:
Sp1 is a critical factor for the monocytic specific expression of human CD14.
J Biol Chem
269:11425,
1994[Abstract/Free Full Text]
67.
Zhang D-E,
Hetherington CJ,
Gonzalez DA,
Chen HM,
Tenen DG:
Regulation of CD14 expression during monocytic differentiation induced with 1alpha,25-Dihydroxyvitamin D3.
J Immunol
153:3276,
1994[Abstract]
68.
Saffer JD,
Jackson SP,
Annarella MB:
Developmental expression of Sp1 in the mouse.
Mol Cell Biol
11:2189,
1991[Abstract/Free Full Text]
69.
Darrow AL,
Rickles RJ,
Pecorino LT,
Strickland S:
Transcription factor Sp1 is important for retinoic acid-induced expression of the tissue plasminogen activator gene during F9 teratocarcinoma cell differentiation.
Mol Cell Biol
10:5883,
1990[Abstract/Free Full Text]
70.
Kim SJ,
Onwuta US,
Lee YI,
Li R,
Botchan MR,
Robbins PD:
The retinoblastoma gene product regulates Sp1-mediated transcription.
Mol Cell Biol
12:2455,
1992[Abstract/Free Full Text]
71.
Udvadia AJ,
Rogers KT,
Higgins PDR,
Murata Y,
Martin KH,
Humphrey PA,
Horowitz JM:
Sp-1 binds promoter elements regulated by the RB protein and Sp-1-mediated transcription is stimulated by RB coexpression.
Proc Natl Acad Sci USA
90:3265,
1993[Abstract/Free Full Text]
72.
Chen LI,
Nishinaka T,
Kwan K,
Kitabayashi I,
Yokoyama K,
Fu YHF,
Grunwald S,
Chiu R:
The retinoblastoma gene product RB stimulates Sp1-mediated transcription by liberating Sp1 from a negative regulator.
Mol Cell Biol
14:4380,
1994[Abstract/Free Full Text]
73.
Hagen G,
Muller S,
Beato M,
Suske G:
Sp1-mediated transcriptional activation is repressed by Sp3.
EMBO J
13:3843,
1994[Medline]
[Order article via Infotrieve]
74.
Zhang R,
Tsai FY,
Orkin SH:
Hematopoietic development of vav(-/-) mouse embryonic stem cells.
Proc Natl Acad Sci USA
91:12755,
1994[Abstract/Free Full Text]
75.
Fischer KD,
Haese A,
Nowock J:
Cooperation of GATA-1 and Sp1 can result in synergistic transcriptional activation or interference.
J Biol Chem
268:23915,
1993[Abstract/Free Full Text]
76.
Pahl HL,
Rosmarin AG,
Tenen DG:
Characterization of the myeloid-specific CD11b promoter.
Blood
79:865,
1992[Abstract/Free Full Text]
77.
Martin F,
Prandini MH,
Thevenon D,
Marguerie G,
Uzan G:
The transcription factor GATA-1 regulates the promoter activity of the platelet glycoprotein-IIb gene.
J Biol Chem
268:21606,
1993[Abstract/Free Full Text]
78.
Lee ME,
Temizer DH,
Clifford JA,
Quertermous T:
Cloning of the GATA-binding protein that regulates endothelin-1 gene expression in endothelial cells.
J Biol Chem
266:16188,
1991[Abstract/Free Full Text]
79.
Zon LI,
Yamaguchi Y,
Yee K,
Albee EA,
Kimura A,
Bennett JC,
Orkin SH,
Ackerman SJ:
Expression of mRNA for the GATA-binding proteins in human eosinophils and basophils: Potential role in gene transcription.
Blood
81:3234,
1993[Abstract/Free Full Text]
80.
Visvader JE,
Elefanty AG,
Strasser A,
Adams JM:
GATA-1 but not SCL induces megakaryocytic differentiation in an early myeloid line.
EMBO J
11:4557,
1992[Medline]
[Order article via Infotrieve]
81.
Kulessa H,
Frampton J,
Graf T:
GATA-1 reprograms avian myelomonocytic cell lines into eosinophils, thromboblasts, and erythroblasts.
Genes Dev
9:1250,
1995[Abstract/Free Full Text]
82.
Ferrero E,
Jiao D,
Tsuberi BZ,
Tesio L,
Rong GW,
Haziot A,
Goyert SM:
Transgenic mice expressing human CD14 are hypersensitive to lipopolysaccharide.
Proc Natl Acad Sci USA
90:2380,
1993[Abstract/Free Full Text]
83. Tenen DG: unpublished data.
84.
Ahne B,
Stratling WH:
Characterization of a myeloid-specific enhancer of the chicken lysozyme gene Major role for an Ets transcription factor-binding site.
J Biol Chem
269:17794,
1994[Abstract/Free Full Text]
85.
Bonifer C,
Vidal M,
Grosveld F,
Sippel AE:
Tissue specific and position independent expression of the complete gene domain for chicken lysozyme in transgenic mice.
EMBO J
9:2843,
1990[Medline]
[Order article via Infotrieve]
86.
Morishita K,
Tsuchiya M,
Asano S,
Kaziro Y,
Nagata S:
Chromosomal gene structure of human myeloperoxidase and regulation of its expression by granulocyte colony-stimulating factor.
J Biol Chem
262:15208,
1987[Abstract/Free Full Text]
87.
Nuchprayoon I,
Meyers S,
Scott LM,
Suzow J,
Hiebert S,
Friedman AD:
PEBP2/CBF, the murine homolog of the human myeloid AML1 and PEBP2beta/CBFbeta proto-oncoproteins, regulates the murine myeloperoxidase and neutrophil elastase genes in immature myeloid cells.
Mol Cell Biol
14:5558,
1994[Abstract/Free Full Text]
88.
Oelgeschlager M,
Nuchprayoon I,
Luscher B,
Friedman AD:
C/EBP, c-Myb, and PU.1 cooperate to regulate the neutrophil elastase promoter.
Mol Cell Biol
16:4717,
1996[Abstract]
89.
Sturrock A,
Franklin KF,
Hoidal JR:
Human proteinase-3 expression is regulated by PU.1 in conjunction with a cytidine-rich element.
J Biol Chem
271:32392,
1996[Abstract/Free Full Text]
90.
Grisolano JL,
Sclar GM,
Ley TJ:
Early myeloid cell-specific expression of the human cathepsin G gene in transgenic mice.
Proc Natl Acad Sci USA
91:8989,
1994[Abstract/Free Full Text]
91.
Shapiro LH,
Ashmun RA,
Roberts WM,
Look AT:
Separate promoters control transcription of the human aminopeptidase N gene in myeloid and intestinal epithelial cells.
J Biol Chem
266:11999,
1991[Abstract/Free Full Text]
92.
Avalos BR:
Molecular analysis of the granulocyte colony-stimulating factor receptor.
Blood
88:761,
1996[Free Full Text]
93.
Rosmarin AG,
Weil SC,
Rosner GL,
Griffin JD,
Arnaout MA,
Tenen DG:
Differential expression of CD11b/CD18 (Mo1) and myeloperoxidase genes during myeloid differentiation.
Blood
73:131,
1989[Abstract/Free Full Text]
94.
Hickstein DD,
Back AL,
Collins SJ:
Regulation of expression of the CD11b and CD18 subunits of the neutrophil adherence receptor during human myeloid differentiation.
J Biol Chem
264:21812,
1989[Abstract/Free Full Text]
95.
Chen HM,
Zhang P,
Voso MT,
Hohaus S,
Gonzalez DA,
Glass CK,
Zhang D-E,
Tenen DG:
Neutrophils and monocytes express high levels of PU.1 (Spi-1) but not Spi-B.
Blood
85:2918,
1995[Abstract/Free Full Text]
96.
Farokhzad OO,
Shelley CS,
Arnaout MA:
Induction of the CD11b gene during activation of the monocytic cell line U937 requires a novel nuclear factor MS-2.
J Immunol
157:5597,
1996[Abstract]
97.
Wu H,
Moulton K,
Horvai A,
Parik S,
Glass CK:
Combinatorial interactions between AP-1 and ets domain proteins contribute to the developmental regulation of the macrophage scavenger receptor gene.
Mol Cell Biol
14:2129,
1994[Abstract/Free Full Text]
98.
Tsukada J,
Saito K,
Waterman WR,
Webb AC,
Auron PE:
Transcription factors NF-IL6 and CREB recognize a common essential site in the human prointerleukin 1 gene.
Mol Cell Biol
14:7285,
1994[Abstract/Free Full Text]
99.
Tsukada J,
Waterman WR,
Koyama Y,
Webb AC,
Auron PE:
A novel STAT-like factor mediates lipopolysaccharide, interleukin 1 (IL-1), and IL-6 signaling and recognizes a gamma interferon activation site-like element in the IL1B gene.
Mol Cell Biol
16:2183,
1996[Abstract]
100.
Kozak M:
An analysis of 5'-noncoding sequences from 699 vertebrate messenger RNAs.
Nucleic Acids Res
15:8125,
1987[Abstract/Free Full Text]
101.
Hehlgans T,
Strominger JL:
Activation of transcription by binding of NF-E1 (YY1) to a newly identified element in the first exon of the human DR alpha gene.
J Immunol
154:5181,
1995[Abstract]
102.
Grosveld F,
van Assendelft GB,
Greaves DR,
Kollias G:
Position-independent, high-level expression of the human beta-globin gene in transgenic mice.
Cell
51:975,
1987[Medline]
[Order article via Infotrieve]
103.
Skalnik DG,
Dorfman D,
Perkins AS,
Jenkins NA,
Copeland NG,
Orkin SH:
Targeting of transgene expression to monocyte/macrophages by the gp91-phox promoter and consequent histiocytic malignancies.
Proc Natl Acad Sci USA
88:8505,
1991[Abstract/Free Full Text]
104.
Greer P,
Maltby V,
Rossant J,
Bernstein A,
Pawson T:
Myeloid expression of the human c-fps/fes proto-oncogene in transgenic mice.
Mol Cell Biol
10:2521,
1990[Abstract/Free Full Text]
105.
Bonifer C,
Yannoutsos N,
Kruger G,
Grosveld F,
Sippel AE:
Dissection of the locus control function located on the chicken lysozyme gene domain in transgenic mice.
Nucleic Acids Res
22:4202,
1994[Abstract/Free Full Text]
106.
Miyazaki T,
Suzuki G,
Yamamura K-I:
The role of macrophages in antigen presentation and T cell tolerance.
Int Immunol
5:1023,
1993[Abstract/Free Full Text]
107.
Jin DI,
Jameson SB,
Reddy MA,
Schenkman D,
Ostrowski MC:
Alterations in differentiation and behavior of monocytic phagocytes in transgenic mice that express dominant suppressors of ras signaling.
Mol Cell Biol
15:693,
1995[Abstract]
108.
Lagasse E,
Weissman IL:
bcl-2 inhibits apoptosis of neutrophils but not their engulfment by macrophages.
J Exp Med
179:1047,
1994[Abstract/Free Full Text]
109.
Brown D,
Kogan S,
Lagasse E,
Weissman IL,
Alcalay M,
Pelicci PG,
Atwater S,
Bishop JM:
A PMLRAR transgene initiates murine acute promyelocytic leukemia.
Proc Natl Acad Sci USA
94:2551,
1997[Abstract/Free Full Text]
110.
Clarke S,
Greaves DR,
Chung LP,
Tree P,
Gordon S:
The human lysozyme promoter directs reporter gene expression to activated myelomonocytic cells in transgenic mice.
Proc Natl Acad Sci USA
93:1434,
1996[Abstract/Free Full Text]
111.
Dziennis S,
Tenen DG:
The CD11b promoter directs high-level expression of reporter genes in macrophages in transgenic mice.
Blood
85:1983,
1995[Free Full Text]
112.
Back A,
East K,
Hickstein D:
Leukocyte integrin CD11b promoter directs expression in lymphocytes and granulocytes in transgenic mice.
Blood
85:1017,
1995[Abstract/Free Full Text]
113.
Early E,
Moore MAS,
Kakizuka A,
Nason-Burchenal K,
Martin P,
Evans RM,
Dmitrovsky E:
Transgenic expression of PML/RAR impairs myelopoiesis.
Proc Natl Acad Sci USA
93:7900,
1996[Abstract/Free Full Text]
114.
De Sepulveda P,
Salaun P,
Maas N,
Andre C,
Panthier JJ:
SARs do not impair position-dependent expression of a kit/lacZ transgene.
Biochem Biophys Res Commun
211:735,
1995[Medline]
[Order article via Infotrieve]
115.
Grisolano JL,
Wesselschmidt RL,
Pelicci PG,
Ley TJ:
Altered myeloid development and acute leukemia in transgenic mice expressing PML-RAR under control of cathepsin G regulatory sequences.
Blood
89:376,
1997[Abstract/Free Full Text]
116.
Pahl HL,
Scheibe RJ,
Zhang D-E,
Chen HM,
Galson DL,
Maki RA,
Tenen DG:
The proto-oncogene PU.1 regulates expression of the myeloid-specific CD11b promoter.
J Biol Chem
268:5014,
1993[Abstract/Free Full Text]
117.
Zhang D-E,
Hetherington CJ,
Chen HM,
Tenen DG:
The macrophage transcription factor PU.1 directs tissue specific expression of the macrophage colony stimulating factor receptor.
Mol Cell Biol
14:373,
1994[Abstract/Free Full Text]
118.
Ray-Gallet D,
Mao C,
Tavitian A,
Moreau-Gachelin F:
DNA binding specificities of Spi-1/PU.1 and Spi-B transcription factors and identification of a Spi-1/Spi-B binding site in the c-fes/c-fps promoter.
Oncogene
11:303,
1995[Medline]
[Order article via Infotrieve]
119.
Heydemann A,
Juang G,
Hennessy K,
Parmacek MS,
Simon MC:
The myeloid cell-specific c-fes promoter is regulated by Sp1, PU.1, and a novel transcription factor.
Mol Cell Biol
16:1676,
1996[Abstract]
120.
Horvai A,
Palinski W,
Wu H,
Moulton KS,
Kalla K,
Glass CK:
Scavenger receptor A gene regulatory elements target gene expression to macrophages and to foam cells of atherosclerotic lesions.
Proc Natl Acad Sci USA
92:5391,
1995[Abstract/Free Full Text]
121.
Krall WJ,
Challita PM,
Perlmutter LS,
Skelton DC,
Kohn DB:
Cells expressing human glucocerebrosidase from a retroviral vector repopulate macrophages and central nervous system microglia after murine bone marrow transplantation.
Blood
83:2737,
1994[Abstract/Free Full Text]
122.
Bauer TR,
Osborne WRA,
Kwok WW,
Hickstein DD:
Expression from leukocyte integrin promoters in retroviral vectors.
Hum Gene Ther
5:709,
1994[Medline]
[Order article via Infotrieve]
123.
Malik P,
Krall WJ,
Yu XJ,
Zhou C,
Kohn DB:
Retroviral-mediated gene expression in human myelomonocytic cells: A comparison of hematopoietic cell promoters to viral promoters.
Blood
86:2993,
1995[Abstract/Free Full Text]
124.
Klemsz MJ,
McKercher SR,
Celada A,
Van Beveren C,
Maki RA:
The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene.
Cell
61:113,
1990[Medline]
[Order article via Infotrieve]
125.
Schuetze S,
Stenberg PE,
Kabat D:
The Ets-related transcription factor PU.1 immortalizes erythroblasts.
Mol Cell Biol
13:5670,
1993[Abstract/Free Full Text]
126.
Moreau-Gachelin F,
Wendling F,
Molina T,
Denis N,
Titeux M,
Grimber G,
Briand P,
Vainchenker W,
Tavitian A:
Spi-1/PU.1 transgenic mice develop multistep erythroleukemias.
Mol Cell Biol
16:2453,
1996[Abstract]
127.
Delgado MD,
Hallier M,
Meneceur P,
Tavitian A,
Moreau-Gachelin F:
Inhibition of friend cells proliferation by spi-1 antisense oligodeoxynucleotides.
Oncogene
9:1723,
1994[Medline]
[Order article via Infotrieve]
128.
Karim FD,
Urness LD,
Thummel CS,
Klemsz MJ,
McKercher SR,
Celada A,
Van Beveren C,
Maki RA,
Gunther CV,
Nye JA,
Graves BJ:
The ETS-domain: A new DNA-binding motif that recognizes a purine-rich core DNA sequence.
Genes Dev
4:1451,
1990[Free Full Text]
129.
Wasylyk B,
Hahn SL,
Giovane A:
The Ets family of transcription factors.
Eur J Biochem
211:7,
1993[Medline]
[Order article via Infotrieve]
130.
Ray D,
Bosselut R,
Ghysdael J,
Mattei MG,
Tavitian A,
Moreau-Gachelin F:
Characterization of Spi-B, a transcription factor related to the putative oncoprotein Spi-1/PU.1.
Mol Cell Biol
12:4297,
1992[Abstract/Free Full Text]
131.
Klemsz MJ,
Maki RA:
Activation of transcription by PU.1 requires both acidic and glutamine domains.
Mol Cell Biol
16:390,
1996[Abstract]
132.
Weintraub SJ,
Chow KN,
Luo RX,
Zhang SH,
He S,
Dean DC:
Mechanism of active transcriptional repression by the retinoblastoma protein.
Nature
375:812,
1995[Medline]
[Order article via Infotrieve]
133.
Kodandapani R,
Pio F,
Ni CZ,
Piccialli G,
Klemsz M,
McKercher S,
Maki RA,
Ely KR:
A new pattern for helix-turn-helix recognition revealed by the PU.1 ETS-domain-DNA complex.
Nature
380:456,
1996[Medline]
[Order article via Infotrieve]
134.
Cheng T,
Shen H,
Giokas D,
Gere J,
Tenen DG,
Scadden DT:
Temporal Mapping of gene expression levels during the differentiation of individual primary hematopoietic cells.
Proc Natl Acad Sci USA
93:13158,
1996[Abstract/Free Full Text]
135.
Hromas R,
Orazi A,
Neiman RS,
Maki R,
Vanbeveran C,
Moore J,
Klemsz M:
Hematopoietic lineage-restricted and stage-restricted expression of the ETS oncogene family member PU.1.
Blood
82:2998,
1993[Abstract/Free Full Text]
136.
Schuetze S,
Paul R,
Gliniak BC,
Kabat D:
Role of the PU.1 transcription factor in controlling differentiation of Friend erythroleukemia cells.
Mol Cell Biol
12:2967,
1992[Abstract/Free Full Text]
137.
Galson DL,
Hensold JO,
Bishop TR,
Schalling M,
D'Andrea AD,
Jones C,
Auron PE,
Housman DE:
Mouse beta-globin DNA-binding protein B1 is identical to a proto-oncogene, the transcription factor Spi-1/PU.1, and is restricted in expression to hematopoietic cells and the testis.
Mol Cell Biol
13:2929,
1993[Abstract/Free Full Text]
138.
Chen HM,
Zhang P,
Radomska HS,
Hetherington CJ,
Zhang D-E,
Tenen DG:
Octamer binding factors and their coactivator can activate the murine PU.1 (spi-1) promoter.
J Biol Chem
271:15743,
1996[Abstract/Free Full Text]
139.
Oka T,
Rairkar A,
Chen JH:
Structural and functional analysis of the regulatory sequences of the ets-1 gene.
Oncogene
6:2077,
1991[Medline]
[Order article via Infotrieve]
140.
Hensold JO,
Stratton CA,
Barth D,
Galson DL:
Expression of the transcription factor, Spi-1 (PU.1), in differentiating murine erythroleukemia cells is regulated post-transcriptionally Evidence for differential stability of transcription factor mrnas following inducer exposure.
J Biol Chem
271:3385,
1996[Abstract/Free Full Text]
141.
Wasylyk C,
Kerckaert JP,
Wasylyk B:
A novel modulator domain of Ets transcription factors.
Genes Dev
6:965,
1992[Abstract/Free Full Text]
142.
Nagulapalli S,
Pongubala JM,
Atchison ML:
Multiple proteins physically interact with PU.1.
J Immunol
155:4330,
1995[Abstract]
143.
Pongubala JM,
Nagulapalli S,
Klemsz MJ,
McKercher SR,
Maki RA,
Atchison ML:
PU.1 recruits a second nuclear factor to a site important for immunoglobulin kappa 3' enhancer activity.
Mol Cell Biol
12:368,
1992[Abstract/Free Full Text]
144.
Pongubala JM,
Van Beveren C,
Nagulapalli S,
Klemsz MJ,
McKercher SR,
Maki RA,
Atchison ML:
Effect of PU.1 phosphorylation on interaction with NF-EM5 and transcriptional activation.
Science
259:1622,
1993[Abstract/Free Full Text]
145.
Eisenbeis CF,
Singh H,
Storb U:
PU.1 is a component of a multiprotein complex which binds an essential site in the murine immunoglobulin lambda-2-4 enhancer.
Mol Cell Biol
13:6452,
1993[Abstract/Free Full Text]
146.
Eisenbeis CF,
Singh H,
Storb U:
Pip, a novel IRF family member, is a lymphoid-specific, PU.1-dependent transcriptional activator.
Genes Dev
9:1377,
1995[Abstract/Free Full Text]
147.
Wang CY,
Petryniak B,
Thompson CB,
Kaelin WG,
Leiden JM:
Regulation of the Ets-related transcription factor Elf-1 by binding to the retinoblastoma protein.
Science
260:1330,
1993[Abstract/Free Full Text]
148.
Chen PL,
Scully P,
Shew JY,
Wang JY,
Lee WH:
Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation.
Cell
58:1193,
1989[Medline]
[Order article via Infotrieve]
149.
Furukawa Y,
DeCaprio JA,
Freedman A,
Kanakura Y,
Nakamura M,
Ernst TJ,
Livingston DM,
Griffin JD:
Expression and state of phosphorylation of the retinoblastoma susceptibility gene product in cycling and noncycling human hematopoietic cells.
Proc Natl Acad Sci USA
87:2770,
1990[Abstract/Free Full Text]
150.
John S,
Reeves RB,
Lin JX,
Child R,
Leiden JM,
Thompson CB,
Leonard WJ:
Regulation of cell-type-specific interleukin-2 receptor alpha-chain gene expression: Potential role of physical interactions between Elf-1, HMG-I(Y), and NF-kappa B family proteins.
Mol Cell Biol
15:1786,
1995[Abstract]
151.
Bassuk AG,
Leiden JM:
A direct physical association between ETS and AP-1 transcription factors in normal human T cells.
Immunity
3:223,
1995[Medline]
[Order article via Infotrieve]
152.
Gauthier JM,
Bourachot B,
Doucas V,
Yaniv M,
Moreau-Gachelin F:
Functional interference between the Spi-1/PU.1 oncoprotein and steroid hormone or vitamin receptors.
EMBO J
12:5089,
1993[Medline]
[Order article via Infotrieve]
153.
Marais R,
Wynne J,
Treisman R:
The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain.
Cell
73:381,
1993[Medline]
[Order article via Infotrieve]
154.
Rao VN,
Reddy ESP:
Elk-1 proteins are phosphoproteins and activators of mitogen-activated protein kinase.
Cancer Res
53:3449,
1993[Abstract/Free Full Text]
155.
Rabault B,
Ghysdael J:
Calcium-induced phosphorylation of ETS1 inhibits its specific DNA binding activity.
J Biol Chem
269:28143,
1994[Abstract/Free Full Text]
156.
Yang BS,
Hauser CA,
Henkel G,
Colman MS,
Van Beveren C,
Stacey KJ,
Hume DA,
Maki RA,
Ostrowski MC:
Ras-mediated phosphorylation of a conserved threonine residue enhances the transactivation activities of c-Ets1 and c-Ets2.
Mol Cell Biol
16:538,
1996[Abstract]
157.
Mao C,
Ray-Gallet D,
Tavitian A,
Moreau-Gachelin F:
Differential phosphorylations of Spi-B and Spi-1 transcription factors.
Oncogene
12:863,
1996[Medline]
[Order article via Infotrieve]
158.
Lodie TA,
Savedra R,
Golenbaock DT,
Van Beveren CP,
Maki RA,
Fenton MJ:
Stimulation of macrophages by LPS alters the phosphorylation state, conformation, and function of PU.1 via activation of casein kinase II.
J Immunol
158:1848,
1997[Abstract]
159.
Celada A,
Borras FE,
Soler C,
Lloberas J,
Klemsz M,
Van Beveren C,
McKercher SC,
Maki RA:
The transcription factor PU.1 is involved in macrophage proliferation.
J Exp Med
184:61,
1996[Abstract/Free Full Text]
160.
Ford AM,
Bennett CA,
Healy LE,
Towatari M,
Greaves MF,
Enver T:
Regulation of the myeloperoxidase enhancer binding proteins PU.1, CEBP, , and during granulocytic-lineage specification.
Proc Natl Acad Sci USA
93:10838,
1996[Abstract/Free Full Text]
161.
McKercher SR,
Torbett BE,
Anderson KL,
Henkel GW,
Vestal DJ,
Baribault H,
Klemsz M,
Feeney AJ,
Wu GE,
Paige CJ,
Maki RA:
Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities.
EMBO J
15:5647,
1996[Medline]
[Order article via Infotrieve]
162.
Olson MC,
Scott EW,
Hack AA,
Su GH,
Tenen DG,
Singh H,
Simon MC:
PU.1 is not essential for early myeloid gene expression but is required for terminal myeloid differentiation.
Immunity
3:703,
1995[Medline]
[Order article via Infotrieve]
163.
Henkel GW,
McKercher SR,
Yamamoto H,
Anderson KL,
Oshima RG,
Maki RA:
PU.1 but not Ets-2 is essential for macrophage development from ES cells.
Blood
88:2917,
1996[Abstract/Free Full Text]
164.
Reddy MA,
Yang BS,
Yue X,
Barnett CJK,
Ross IL,
Sweet MJ,
Hume DA,
Ostrowski MC:
Opposing actions of c-ets/PU.1 and c-myb protooncogene products in regulating the macrophage-specific promoters of the human and mouse colony-stimulating factor-1 receptor (c-fms) genes.
J Exp Med
180:2309,
1994[Abstract/Free Full Text]
165.
Hallier M,
Tavitian A,
Moreau-Gachelin F:
The transcription factor Spi-1/PU.1 binds RNA and interferes with the RNA-binding protein p54(nrb).
J Biol Chem
271:11177,
1996[Abstract/Free Full Text]
166.
Moulton KS,
Semple K,
Wu H,
Glass CK:
Cell-specific expression of the macrophage scavenger receptor gene is dependent on PU.1 and a composite AP-1/ets motif.
Mol Cell Biol
14:4408,
1994[Abstract/Free Full Text]
167.
Kola I,
Brookes S,
Green AR,
Garber R,
Tymms M,
Papas TS,
Seth A:
The Ets1 transcription factor is widely expressed during murine embryo development and is associated with mesodermal cells involved in morphogenetic processes such as organ formation.
Proc Natl Acad Sci USA
90:7588,
1993[Abstract/Free Full Text]
168.
Klemsz MJ,
Maki RA,
Papayannopoulou T,
Moore J,
Hromas R:
Characterization of the ets oncogene family member, fli-1.
J Biol Chem
268:5769,
1993[Abstract/Free Full Text]
169.
Ross IL,
Dunn TL,
Yue X,
Roy S,
Barnett CJK,
Hume DA:
Comparison of the expression and function of the transcription factor PU.1 (Spi-1 proto-oncogene) between murine macrophages and B lymphocytes.
Oncogene
9:121,
1994[Medline]
[Order article via Infotrieve]
170.
Rosmarin AG,
Caprio DG,
Kirsch DG,
Handa H,
Simkevich CP:
GABP and PU.1 compete for binding, yet cooperate to increase CD18 (2 leukocyte integrin) transcription.
J Biol Chem
270:23627,
1995[Abstract/Free Full Text]
171.
Golub TR,
Barker GF,
Lovett M,
Gilliland DG:
Fusion of PDGF receptor beta to a novel ETS-like gene, Tel, in chronic myelomonocytic leukemia with t(5:12) chromosomal translocation.
Cell
77:307,
1994[Medline]
[Order article via Infotrieve]
172.
Golub TR,
Barker GF,
Bohlander SK,
Hiebert SW,
Ward DC,
Brayward P,
Morgan E,
Raimondi SC,
Rowley JD,
Gilliland DG:
Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia.
Proc Natl Acad Sci USA
92:4917,
1995[Abstract/Free Full Text]
173. Golub TR, Mclean T, Stegmaier K, Carroll M, Tomasson M, Gilliland DG: The TEL gene and human leukemia. Bba-Rev Cancer 1288:M7, 1996
174.
Johnson PF,
Landschulz WH,
Graves BJ,
McKnight SL:
Identification of a rat liver nuclear protein that binds to the enhancer core element of three animal viruses.
Genes Dev
1:133,
1987[Abstract/Free Full Text]
175.
Landschulz WH,
Johnson PF,
Adashi EY,
Graves BJ,
McKnight SL:
Isolation of a recombinant copy of the gene encoding C/EBP.
Genes Dev
2:786,
1988[Abstract/Free Full Text]
176.
Landschulz WH,
Johnson PF,
McKnight SL:
The DNA binding domain of the rat liver nuclear protein C/EBP is bipartite.
Science
243:1681,
1989[Abstract/Free Full Text]
177.
Johnson PF,
McKnight SL:
Eukaryotic transcriptional regulatory proteins.
Annu Rev Biochem
58:799,
1989[Medline]
[Order article via Infotrieve]
178.
Vallejo M,
Ron D,
Miller CP,
Habener JF:
C/ATF, a member of the activating transcription factor family of DNA-binding proteins, dimerizes with CAAT/enhancer-binding proteins and directs their binding to cAMP response elements.
Proc Natl Acad Sci USA
90:4679,
1993[Abstract/Free Full Text]
179.
Cao Z,
Umek RM,
McKnight SL:
Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells.
Genes Dev
5:1538,
1991[Abstract/Free Full Text]
180.
Lin FT,
Lane MD:
CCAAT/enhancer binding protein is sufficient to initiate the 3T3-L1 adipocyte differentiation program.
Proc Natl Acad Sci USA
91:8757,
1994[Abstract/Free Full Text]
181.
Hendricks-Taylor LR,
Darlington GJ:
Inhibition of cell proliferation by C/EBP alpha occurs in many cell types, does not require the presence of p53 or Rb, and is not affected by large T-antigen.
Nucleic Acids Res
23:4726,
1995[Abstract/Free Full Text]
182.
Watkins PJ,
Condreay JP,
Huber BE,
Jacobs SJ,
Adams DJ:
Impaired proliferation and tumorigenicity induced by CCAAT/enhancer-binding protein.
Cancer Res
56:1063,
1996[Abstract/Free Full Text]
183.
Timchenko NA,
Wilde M,
Nakanishi M,
Smith JR,
Darlington GJ:
CCAAT/enhancer-binding protein (C/EBP) inhibits cell proliferation though the p21 (WAF-1/CIP-1/SDI-1) protein.
Genes Dev
10:804,
1996[Abstract/Free Full Text]
184.
Williams SC,
Cantwell CA,
Johnson PF:
A family of C/EBP-related proteins capable of forming covalently linked leucine zipper dimers in vitro.
Genes Dev
5:1553,
1991[Abstract/Free Full Text]
185.
Akira S,
Isshiki H,
Sugita T,
Tanabe O,
Kinoshita S,
Nishio Y,
Nakajima T,
Hirano T,
Kishimoto T:
A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family.
EMBO J
9:1897,
1990[Medline]
[Order article via Infotrieve]
186.
Chumakov AM,
Griller I,
Chumakova E,
Chih D,
Slater J,
Koeffler HP:
Cloning of the novel human myeloid-cell-specific C/EBP-epsilon transcription factor.
Mol Cell Biol
17:1375,
1997[Abstract]
187.
Antonson P,
Stellan B,
Yamanaka R,
Xanthopoulos KG:
A novel human CCAAT/enhancer binding protein gene, C/EBP, is expressed in cells of lymphoid and myeloid lineages and is localized on chromsome 14q11.2 close to the T-cell receptor / locus.
Genomics
35:30,
1996[Medline]
[Order article via Infotrieve]
188.
Descombes P,
Schibler U:
A liver-enriched transcriptional activator protein, LAP, and a transcriptional inhibitory protein, LIP, are translated from the same mRNA.
Cell
67:569,
1991[Medline]
[Order article via Infotrieve]
189.
Ossipow V,
Descombes P,
Schibler U:
CCAAT/enhancer-binding protein mRNA is translated into multiple proteins with different transcription activation potentials.
Proc Natl Acad Sci USA
90:8219,
1993[Abstract/Free Full Text]
190.
Ron D,
Habener JF:
CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription.
Genes Dev
6:439,
1992[Abstract/Free Full Text]
191.
Friedman AD:
GADD153/CHOP, a DNA damage-inducible protein, reduced CAAT/enhancer binding protein activities and increased apoptosis in 32D c13 myeloid cells.
Cancer Res
56:3250,
1996[Abstract/Free Full Text]
192.
Christy RJ,
Kaestner KH,
Geiman DE,
Lane MD:
CCAAT/enhancer binding protein gene promoter: Binding of nuclear factors during differentiation of 3T3-L1 preadipocytes.
Proc Natl Acad Sci USA
88:2593,
1991[Abstract/Free Full Text]
193.
Li LH,
Nerlov C,
Prendergast G,
MacGregor D,
Ziff EB:
c-Myc represses transcription in vivo by a novel mechanism dependent on the initiator element and Myc box II.
EMBO J
13:4070,
1994[Medline]
[Order article via Infotrieve]
194.
Timchenko N,
Wilson DR,
Taylor LR,
Abdelsayed S,
Wilde M,
Sawadogo M,
Darlington GJ:
Autoregulation of the human C/EBP alpha gene by stimulation of upstream stimulatory factor binding.
Mol Cell Biol
15:1192,
1995[Abstract]
195.
Scott LM,
Civin CI,
Rorth P,
Friedman AD:
A novel temporal expression pattern of three C/EBP family members in differentiating myelomonocytic cells.
Blood
80:1725,
1992[Abstract/Free Full Text]
196.
Katz S,
Kowenzleutz E,
Muller C,
Meese K,
Ness SA,
Leutz A:
The NF-M transcription factor is related to C/EBP-beta and plays a role in signal transduction, differentiation and leukemogenesis of avian myelomonocytic cells.
EMBO J
12:1321,
1993[Medline]
[Order article via Infotrieve]
197.
Ness SA,
Kowenzleutz E,
Casini T,
Graf T,
Leutz A:
Myb and NF-M Combinatorial activators of myeloid genes in heterologous cell types.
Genes Dev
7:749,
1993[Abstract/Free Full Text]
198.
Sterneck E,
Muller C,
Katz S,
Leutz A:
Autocrine growth induced by kinase type oncogenes in myeloid cells requires AP-1 and NF-M, a myeloid specific, C/EBP-like factor.
EMBO J
11:115,
1992[Medline]
[Order article via Infotrieve]
199.
Haas JG,
Strobel M,
Leutz A,
Wendelgass P,
Muller C,
Sterneck E,
Riethmuller G,
Ziegler-Heitbrock HW:
Constitutive monocyte-restricted activity of NF-M, a nuclear factor that binds to a C/EBP motif.
J Immunol
149:237,
1992[Abstract]
200.
Natsuka S,
Akira S,
Nishio Y,
Hashimoto S,
Sugita T,
Isshiki H,
Kishimoto T:
Macrophage differentiation-specific expression of NF-IL6, a transcription factor for interleukin-6.
Blood
79:460,
1992[Abstract/Free Full Text]
201.
Landschulz WH,
Johnson PF,
McKnight SL:
The leucine zipper: A hypothetical structure common to a new class of DNA binding proteins.
Science
240:1759,
1988[Abstract/Free Full Text]
202.
Williams SC,
Baer M,
Dillner AJ,
Johnson PF:
CRP2 (C/EBP beta) contains a bipartite regulatory domain that controls transcriptional activation, DNA binding and cell specificity.
EMBO J
14:3170,
1995[Medline]
[Order article via Infotrieve]
203.
Friedman AD,
McKnight SL:
Identification of two polypeptide segments of CCAAT/enhancer-binding protein required for transcriptional activation of the serum albumin gene.
Genes Dev
4:1416,
1990[Abstract/Free Full Text]
204.
Jones KA,
Kadonaga JT,
Rosenfeld PJ,
Kelly TJ,
Tjian R:
A cellular DNA-binding protein that activates eukaryotic transcription and DNA replication.
Cell
48:79,
1987[Medline]
[Order article via Infotrieve]
205.
Dorn A,
Bollekens J,
Staub A,
Benoist C,
Mathis D:
A multiplicity of CCAAT box-binding proteins.
Cell
50:863,
1987[Medline]
[Order article via Infotrieve]
206.
van Huijsduijnen RH,
Li XY,
Black D,
Matthes H,
Benoist C,
Mathis D:
Co-evolution from yeast to mouse: cDNA cloning of the two NF-Y (CP- 1/CBF) subunits.
EMBO J
9:3119,
1990[Medline]
[Order article via Infotrieve]
207.
Maity SN,
Sinha S,
Ruteshouser EC,
de Crombrugghe B:
Three different polypeptides are necessary for DNA binding of the mammalian heteromeric CCAAT binding factor.
J Biol Chem
267:16574,
1992[Abstract/Free Full Text]
208.
Pope RM,
Leutz A,
Ness SA:
C/EBP beta regulation of the tumor necrosis factor alpha gene.
J Clin Invest
94:1449,
1994
209.
Osada S,
Yamamoto H,
Nishihara T,
Imagawa M:
DNA binding specificity of the CCAAT/enhancer-binding protein transcription factor family.
J Biol Chem
271:3891,
1996[Abstract/Free Full Text]
210.
Stein B,
Cogswell PC,
Baldwin AS Jr:
Functional and physical associations between NF-kB and C/EBP family members: A Rel domain-bZIP interaction.
Mol Cell Biol
13:3964,
1993[Abstract/Free Full Text]
211.
Diehl JA,
Hannink M:
Identification of a C/EBP-Rel complex in avian lymphoid cells.
Mol Cell Biol
14:6635,
1994[Abstract/Free Full Text]
212.
Lee YH,
Yano M,
Liu SY,
Matsunaga E,
Johnson PF,
Gonzalez FJ:
A novel cis-acting element controlling the rat CYP2D5 gene and requiring cooperativity between C/EBP beta and an Sp1 factor.
Mol Cell Biol
14:1383,
1994[Abstract/Free Full Text]
213.
Chen PL,
Riley DJ,
Chen-Kiang S,
Lee WH:
Retinoblastoma protein directly interacts with and activates the transcription factor NF-IL6.
Proc Natl Acad Sci USA
93:465,
1995[Abstract/Free Full Text]
214.
Hsu W,
Kerppola TK,
Chen P,
Curran T,
Chen-Kiang S:
Fos and jun repress transcription activation by NF-IL6 through association at the basic zipper region.
Mol Cell Biol
14:268,
1993[Abstract/Free Full Text]
215.
Zhang D-E,
Hetherington CJ,
Meyers S,
Rhoades KL,
Larson CJ,
Chen HM,
Hiebert SW,
Tenen DG:
CCAAT enhancer binding protein (C/EBP) and AML1 (CBF2) synergistically activate the M-CSF receptor promoter.
Mol Cell Biol
16:1231,
1996[Abstract]
216.
Chen PL,
Riley DJ,
Chen YM,
Lee WH:
Retinoblastoma protein positively regulates terminal adipocyte differentiation through direct interaction with C/EBPs.
Gene Dev
10:2794,
1996[Abstract/Free Full Text]
217.
Wang ND,
Finegold MJ,
Bradley A,
Ou CN,
Abdelsayed SV,
Wilde MD,
Taylor LR,
Wilson DR,
Darlington GJ:
Impaired energy homeostasis in C/EBP knockout mice.
Science
269:1108,
1995[Abstract/Free Full Text]
218.
Flodby P,
Barlow C,
Kylefjord H,
Ahrlund-Richter L,
Xanthopoulos KG:
Increased hepatic cell proliferation and lung abnormalities in mice deficient in CCAAT/enhancer binding protein .
J Biol Chem
271:24753,
1996[Abstract/Free Full Text]
219.
Lui F,
Wu HY,
Wesselschmidt RL,
Kornaga T,
Link DC:
Impaired production and increased apoptosis of neutrophils in granulocyte colony-stimulating factor receptor-deficient mice.
Immunity
5:491,
1996[Medline]
[Order article via Infotrieve]
220.
Metz R,
Ziff E:
cAMP stimulates the C/EBP-related transcription factor NFIL-6 to trans-locate to the nucleus and induce c-fos transcription.
Genes Dev
5:1754,
1991[Abstract/Free Full Text]
221.
Wegner M,
Cao Z,
Rosenfeld MG:
Calcium-regulated phosphorylation within the leucine zipper of C/EBP beta.
Science
256:370,
1992[Abstract/Free Full Text]
222.
Tanaka T,
Akira S,
Yoshida K,
Umemoto M,
Yoneda Y,
Shirafuji N,
Fujiwara H,
Suematsu S,
Yoshida N,
Kishimoto T:
Targeted disruption of the NF-IL6 gene discloses its essential role in bacteria killing and tumor cytotoxicity by macroophages.
Cell
80:353,
1995[Medline]
[Order article via Infotrieve]
223.
Screpanti I,
Romani L,
Musiani P,
Modesti A,
Fattori E,
Lazzaro D,
Sellitto C,
Scarpa S,
Bellavia D,
Lattanzio G,
Bistoni F,
Frati L,
Cortese R,
Gulino A,
Ciliberto G,
Costantini F,
Poli V:
Lymphoproliferative disorder and imbalanced T-helper response in C/EBP beta-deficient mice.
EMBO J
14:1932,
1995[Medline]
[Order article via Infotrieve]
224.
Akira S,
Yoshida K,
Tanaka T,
Taga T,
Kishimoto T:
Targeted disruption of the IL-6 related genes: gp130 and NF-IL-6.
Immunol Rev
148:221,
1995[Medline]
[Order article via Infotrieve]
225.
Crozat A,
Aman P,
Mandahl N,
Ron D:
Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma.
Nature
363:640,
1993[Medline]
[Order article via Infotrieve]
226.
Hendricks-Taylor LR,
Bachinski LL,
Siciliano MJ,
Fertitta A,
Trask B,
de Jong PJ,
Ledbetter DH,
Darlington GJ:
The CCAAT/enhancer binding protein (C/EBP alpha) gene (CEBPA) maps to human chromosome 19q13.1 and the related nuclear factor NF-IL6 (C/EBP beta) gene (CEBPB) gene maps to human chrosome 20q13.1.
Genomics
14:12,
1992[Medline]
[Order article via Infotrieve]
227.
Barberis A,
Superti-Furga G,
Busslinger M:
Mutually exclusive interaction of the CCAAT-binding factor and of a displacement protein with overlapping sequences of a histone gene promoter.
Cell
50:347,
1987[Medline]
[Order article via Infotrieve]
228.
Skalnik DG,
Strauss EC,
Orkin SH:
CCAAT displacement protein as a repressor of the myelomonocytic-specific gp91-phox gene promoter.
J Biol Chem
266:16736,
1991[Abstract/Free Full Text]
229.
Neufeld EJ,
Skalnik DG,
Lievens PM,
Orkin SH:
Human CCAAT displacement protein is homologous to the Drosophila homeoprotein, cut.
Nat Genet
1:50,
1992[Medline]
[Order article via Infotrieve]
230. Khanna-Gupta A, Zibello T, Neufeld E, Berliner N: CCAAT displacement protein (CDP) recognizes a silencer element within the lactoferrin gene promoter. Blood (submitted)
231.
He GP,
Mulse A,
Li AW,
Ro HS:
A eukaryotic transcriptional repressor with carboxypeptidase activity.
Nature
378:92,
1995[Medline]
[Order article via Infotrieve]
232.
Wang S,
Wang Q,
Crute BE,
Melnikova IN,
Keller SR,
Speck NA:
Cloning and characterization of subunits of the T-cell receptor and murine leukemia virus enhancer core-binding factor.
Mol Cell Biol
13:3324,
1993[Abstract/Free Full Text]
233.
Ogawa E,
Maruyama M,
Kagoshima H,
Inuzuka M,
Lu J,
Satake M,
Shigesada K,
Ito Y:
PEBP2/PEA2 represents a family of transcription factors homologous to the products of the Drosophila Runt gene and the human AML1 gene.
Proc Natl Acad Sci USA
90:6859,
1993[Abstract/Free Full Text]
234.
Levanon D,
Negreanu V,
Bernstein Y,
Baram I,
Avivi L,
Groner Y:
AML1, AML2, and AML3, the human members of the runt domain gene-family: cDNA structure, expression, and chromosomal localization.
Genomics
23:425,
1994[Medline]
[Order article via Infotrieve]
235.
Tanaka T,
Tanaka K,
Ogawa S,
Kurokawa M,
Mitani K,
Nishida J,
Shibata Y,
Yazaki Y,
Hirai H:
An acute myeloid leukemia gene, AML1, regulates hemopoietic myeloid cell differentiation and transcriptional activation antagonistically by two alternative spliced forms.
EMBO J
14:341,
1995[Medline]
[Order article via Infotrieve]
236.
Takahashi A,
Satake M,
Yamaguchiiwai Y,
Bae SC,
Lu J,
Maruyama M,
Zhang YW,
Oka H,
Arai N,
Arai K,
Ito Y:
Positive and negative regulation of granulocyte-macrophage colony-stimulating factor promoter activity by AML1- related transcription factor, PEBP2.
Blood
86:607,
1995[Abstract/Free Full Text]
237.
Miyoshi H,
Ohira M,
Shimizu K,
Mitani K,
Hirai H,
Imai T,
Yokoyama K,
Soeda E,
Ohki M:
Alternative splicing and genomic structure of the AML1 gene involved in acute myeloid leukemia.
Nucleic Acids Res
23:2762,
1995[Abstract/Free Full Text]
238.
Meyers S,
Lenny N,
Hiebert SW:
The t(8:21) fusion protein interferes with AML-1B-dependent transcriptional activation.
Mol Cell Biol
15:1974,
1995[Abstract]
239.
Kagoshima H,
Shigesada K,
Satake M,
Ito Y,
Miyoshi H,
Ohki M,
Pepling M,
Gergen P:
The Runt domain identifies a new family of heteromeric transcriptional regulators.
Trends Genet
9:338,
1993[Medline]
[Order article via Infotrieve]
240.
Kania MA,
Bonner AS,
Duffy JB,
Gergen JP:
The Drosophila segmentation gene runt encodes a novel nuclear regulatory protein that is also expressed in the developing nervous system.
Genes Dev
4:1701,
1990[Abstract/Free Full Text]
241.
Meyers S,
Downing JR,
Hiebert SW:
Identification of AML-1 and the (8; 21) translocation protein (AML-1/ETO) as sequence-specific DNA-binding proteins The Runt homology domain is required for DNA binding and protein-protein interactions.
Mol Cell Biol
13:6336,
1993[Abstract/Free Full Text]
242.
Tanaka K,
Tanaka T,
Ogawa S,
Kurokawa M,
Mitani K,
Yazaki Y,
Hirai H:
Increased expression of AML1 during retinoic-acid-induced differentiation of U937 cells.
Biochem Biophys Res Commun
211:1023,
1995[Medline]
[Order article via Infotrieve]
243.
Zhu X,
Yeadon JE,
Burden SJ:
AML1 is expressed in skeletal muscle and is regulated by innervation.
Mol Cell Biol
14:8051,
1994[Abstract/Free Full Text]
244.
Wang Q,
Stacy T,
Miller JD,
Lewis AF,
Gu T-L,
Huang X,
Bushweller JH,
Bories JC,
Alt FW,
Ryan G,
Liu PP,
Wynshaw-Boris A,
Binder M,
Marin-Padilla M,
Sharpe AH,
Speck NA:
The CBF subunit is essential for CBF2 (AML1) function in vivo.
Cell
87:697,
1996[Medline]
[Order article via Infotrieve]
245.
Zhang D-E,
Hohaus S,
Voso MT,
Chen HM,
Smith LT,
Hetherington CJ,
Tenen DG:
Function of PU.1 (Spi-1), C/EBP, and AML1 in early myelopoiesis: Regulation of multiple myeloid CSF receptor promoters.
Curr Top Microbiol Immunol
211:137,
1996[Medline]
[Order article via Infotrieve]
246.
Giese K,
Kingsley C,
Kirshner JR,
Grosschedl R:
Assembly and function of a TCR alpha enhancer complex is dependent on LEF-1-induced DNA bending and multiple protein-protein interactions.
Genes Dev
9:995,
1995[Abstract/Free Full Text]
247.
Hernandez-Munain C,
Krangel MS:
Regulation of the T-cell receptor delta enhancer by functional cooperation between c-Myb and core-binding factors.
Mol Cell Biol
14:473,
1994[Abstract/Free Full Text]
248.
Wotton D,
Ghysdael J,
Wang S,
Speck NA,
Owen MJ:
Cooperative binding of Ets-1 and core binding factor to DNA.
Mol Cell Biol
14:840,
1994[Abstract/Free Full Text]
249.
Sun WW,
Graves BJ,
Speck NA:
Transactivation of the Moloney murine leukemia virus and T-cell receptor beta-chain enhancers by cbf and ets requires intact binding sites for both proteins.
J Virol
69:4941,
1995[Abstract]
250.
Tanaka T,
Kurokawa M,
Ueki K,
Tanaka K,
Imai Y,
Mitani K,
Okazaki K,
Sagata N,
Yazaki Y,
Shibata Y,
Kadowaki T,
Hirai H:
The extracellular signal-regulated kinase pathway phosphorylates AML1, an acute myeloid leukemia gene product, and potentially regulates its transactivation ability.
Mol Cell Biol
16:3967,
1996[Abstract]
251.
Miyoshi H,
Kozu T,
Shimizu K,
Enomoto K,
Maseki N,
Kaneko Y,
Kamada N,
Ohki M:
The t(8-21) translocation in acute myeloid leukemia results in production of an AML1-MTG8 fusion transcript.
EMBO J
12:2715,
1993[Medline]
[Order article via Infotrieve]
252.
Erickson P,
Gao J,
Chang KS,
Look T,
Whisenant E,
Raimondi S,
Lasher R,
Trujillo J,
Rowley J,
Drabkin H:
Identification of breakpoints in t(8; 21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt.
Blood
80:1825,
1992[Abstract/Free Full Text]
253.
Mitani K,
Ogawa S,
Tanaka T,
Miyoshi H,
Kurokawa M,
Mano H,
Yazaki Y,
Ohki M,
Hirai H:
Generation of the AML1-EVI-1 fusion gene in the t(3; 21)(q26; q22) causes blastic crisis in chronic myelocytic leukemia.
EMBO J
13:504,
1994[Medline]
[Order article via Infotrieve]
254.
Nucifora G,
Begy CR,
Erickson P,
Drabkin HA,
Rowley JD:
The 3; 21 translocation in myelodysplasia results in a fusion transcript between the AML1 gene and the gene for EAP, a highly conserved protein associated with the Epstein-Barr virus small RNA EBER-1.
Proc Natl Acad Sci USA
90:7784,
1993[Abstract/Free Full Text]
255.
Romana SP,
Mauchauffe M,
Le Coniat M,
Chumakov I,
Le Paslier D,
Berger R,
Bernard OA:
The t(12; 21) of acute lymphoblastic leukemia results in a tel-AML1 gene fusion.
Blood
85:3662,
1995[Abstract/Free Full Text]
256.
Nucifora G,
Birn DJ,
Espinosa R,
Erickson P,
LeBeau MM,
Roulston D,
McKeithan TW,
Drabkin H,
Rowley JD:
Involvement of the AML1 gene in the t(3; 21) in therapy-related leukemia and in chronic myeloid leukemia in blast crisis.
Blood
81:2728,
1993[Abstract/Free Full Text]
257.
Liu P,
Tarle SA,
Hajra A,
Claxton DF,
Marlton P,
Freedman M,
Siciliano MJ,
Collins FS:
Fusion between transcription factor CBF-beta/PEBP2-beta and a myosin heavy chain in acute myeloid leukemia.
Science
261:1041,
1993[Abstract/Free Full Text]
258.
Frank R,
Zhang J,
Uchida H,
Meyers S,
Hiebert SW,
Nimer SD:
The AML1/ETO fusion protein blocks transactivation of the GM-CSF promoter by AML1B.
Oncogene
11:2667,
1995[Medline]
[Order article via Infotrieve]
259.
Hiebert SW,
Sun W,
Davis JN,
Golub T,
Shurtleff S,
Buijs A,
Downing JR,
Grosveld G,
Roussell MF,
Gilliland DG,
Lenny N,
Meyers S:
The t(12; 21) translocation converts AML-1B from an activator to a repressor of transcription.
Mol Cell Biol
16:1349,
1996[Abstract]
260.
Taylor DS,
Laubach JP,
Nathan DG,
Mathey-Prevot B:
Cooperation between core binding factor and adjacent promoter elements contributes to the tissue-specific expression of interleukin-3.
J Biol Chem
271:14020,
1996[Abstract/Free Full Text]
261.
Uchida H,
Zhang J,
Nimer SD:
AML1A and AML1B can transactivate the human IL-3 promoter.
J Immunol
158:2251,
1997[Abstract]
262.
Friedman AD,
Britosbray M,
Suzow J:
The murine myeloperoxidase gene contains a bipartite distal enhancer, including a novel region regulated by PEBP2/CBF.
Leuk Res
20:809,
1996[Medline]
[Order article via Infotrieve]
263.
Rhoades KL,
Hetherington CJ,
Rowley JD,
Hiebert SW,
Nucifora G,
Tenen DG,
Zhang D-E:
Synergistic up-regulation of the myeloid-specific promoter for the macrophage colony-stimulating factor receptor by AML1 and the t(8; 21) fusion protein may contribute to leukemogenesis.
Proc Natl Acad Sci USA
93:11895,
1996[Abstract/Free Full Text]
264.
Matsushime H,
Roussel MF,
Ashmun RA,
Sherr CJ:
Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle.
Cell
65:701,
1991[Medline]
[Order article via Infotrieve]
265.
Borycki AG,
Foucrier J,
Saffar L,
Leibovitch SA:
Repression of the CSF-1 receptor (c-fms proto-oncogene product) by antisense transfection induces G1-growth arrest in L6 alpha 1 rat myoblasts.
Oncogene
10:1799,
1995[Medline]
[Order article via Infotrieve]
266.
Sherr CJ,
Rettenmier CW,
Sacca R,
Roussel MF,
Look AT,
Stanley ER:
The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF-1.
Cell
41:665,
1985[Medline]
[Order article via Infotrieve]
267.
Roussel MF,
Dull TJ,
Rettenmier CW,
Ralph P,
Ullrich A,
Sherr CJ:
Transforming potential of the c-fms proto-oncogene (CSF-1 receptor).
Nature
325:549,
1987[Medline]
[Order article via Infotrieve]
268.
Gisselbrecht S,
Fichelson S,
Sola B,
Bordereaux D,
Hampe A,
Andre C,
Galibert F,
Tambourin P:
Frequent c-fms activation by proviral insertion in mouse myeloblastic leukaemias.
Nature
329:259,
1987[Medline]
[Order article via Infotrieve]
269.
Yergeau DA,
Hetherington CJ,
Wang Q,
Zhang P,
Sharpe AH,
Binder M,
Marin-Padilla M,
Tenen DG,
Speck NA,
Zhang D-E:
Embryonic lethality and impairment of hemtopoiesis in mice heterozygous for an AML1-ETO fusion gene.
Nat Genet
15:303,
1997[Medline]
[Order article via Infotrieve]
270.
Castilla LH,
Wijmenga C,
Wang Q,
Stacy T,
Speck NA,
Eckhaus M,
Marin-Padilla M,
Collins FS,
Wynshaw-Boris A,
Liu PP:
Failure of embryonic hematopoiesis and lethal hemorrhages in mouse embryos heterozygous for a knocked-in leukemia gene CBF-MYH11.
Cell
87:687,
1996[Medline]
[Order article via Infotrieve]
271.
Hodges RE,
Sauberlich HE,
Canham JE,
Wallace DL,
Rucker RB,
Mejia LA,
Mohanram M:
Hematopoietic studies in vitamin A deficiency.
Am J Clin Nutr
31:876,
1978[Abstract/Free Full Text]
272.
Douer D,
Koeffler HP:
Retinoic acid enhances colony-stimulating factor-induced clonal growth of normal human myeloid progenitor cells in vitro.
Exp Cell Res
138:193,
1982[Medline]
[Order article via Infotrieve]
273.
Gratas C,
Menot ML,
Dresch C,
Chomienne C:
Retinoid acid supports granulocytic but not erythroid differentiation of myeloid progenitors in normal bone marrow cells.
Leukemia
7:1156,
1993[Medline]
[Order article via Infotrieve]
274.
Breitman TR,
Selonick SE,
Collins SJ:
Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid.
Proc Natl Acad Sci USA
77:2936,
1980[Abstract/Free Full Text]
275.
Breitman TR,
Collins SJ,
Keene BR:
Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acid.
Blood
57:1000,
1981[Abstract/Free Full Text]
276.
Mangelsdorf DJ,
Evans RM:
The RXR heterodimers and orphan receptors.
Cell
83:841,
1995[Medline]
[Order article via Infotrieve]
277.
Evans RM:
The steroid and thyroid hormone receptor superfamily.
Science
240:889,
1988[Abstract/Free Full Text]
278.
Glass CK,
DiRenzo J,
Kurokawa R,
Han ZH:
Regulation of gene expression by retinoic acid receptors.
DNA Cell Biol
10:623,
1991[Medline]
[Order article via Infotrieve]
279.
de The H,
Marchio A,
Tiollais P,
Dejean A:
Differential expression and ligand regulation of the retinoic acid receptor alpha and beta genes.
EMBO J
8:429,
1989[Medline]
[Order article via Infotrieve]
280.
Gallagher RE,
Said F,
Pua I,
Papenhausen PR,
Paietta E,
Wiernik PH:
Expression of retinoic acid receptor-alpha mRNA in human leukemia cells with variable responsiveness to retinoic acid.
Leukemia
3:789,
1989[Medline]
[Order article via Infotrieve]
281.
Largman C,
Detmer K,
Corral JC,
Hack FM,
Lawrence HJ:
Expression of retinoic acid receptor alpha mRNA in human leukemia cells.
Blood
74:99,
1989[Abstract/Free Full Text]
282.
Umesono K,
Murakami KK,
Thompson CC,
Evans RM:
Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors.
Cell
65:1255,
1991[Medline]
[Order article via Infotrieve]
283.
Naar AM,
Boutin JM,
Lipkin SM,
Yu VC,
Holloway JM,
Glass CK,
Rosenfeld MG:
The orientation and spacing of core DNA-binding motifs dictate selective transcriptional responses to three nuclear receptors.
Cell
65:1267,
1991[Medline]
[Order article via Infotrieve]
284.
Gudas LJ:
Retinoids and vertebrate development.
J Biol Chem
269:15399,
1994[Abstract/Free Full Text]
285.
Mangelsdorf DJ,
Borgmeyer U,
Heyman RA,
Zhou JY,
Ong ES,
Oro AE,
Kakizuka A,
Evans RM:
Characterization of three RXR genes that mediate the action of 9-cis retinoic acid.
Genes Dev
6:329,
1992[Abstract/Free Full Text]
286.
Collins SJ,
Robertson KA,
Mueller L:
Retinoic acid-induced granulocytic differentiation of HL-60 myeloid leukemia cells is mediated directly through the retinoic acid receptor (RAR-alpha).
Mol Cell Biol
10:2154,
1990[Abstract/Free Full Text]
287.
Robertson KA,
Emami B,
Collins SJ:
Retinoic acid-resistant HL-60R cells harbor a point mutation in the retinoic acid receptor ligand-binding domain that confers dominant negative activity.
Blood
80:1885,
1992[Abstract/Free Full Text]
288.
Robertson KA,
Emami B,
Mueller L,
Collins SJ:
Multiple members of the retinoic acid receptor family are capable of mediating the granulocytic differentiation of HL-60 cells.
Mol Cell Biol
12:3743,
1992[Abstract/Free Full Text]
289.
Tsai S,
Bartelmez S,
Heyman R,
Damm K,
Evans R,
Collins SJ:
A mutated retinoic acid receptor-alpha exhibiting dominant-negative activity alters the lineage development of a multipotent hematopoietic cell line.
Genes Dev
6:2258,
1992[Abstract/Free Full Text]
290.
Warrell RP Jr,
de The H,
Wang ZY,
Degos L:
Acute promyelocytic leukemia.
N Engl J Med
329:177,
1993[Free Full Text]
291.
de The H,
Chomienne C,
Lanotte M,
Degos L,
Dejean A:
The t(15; 17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus.
Nature
347:558,
1990[Medline]
[Order article via Infotrieve]
292.
Chang KS,
Stass SA,
Chu DT,
Deaven LL,
Trujillo JM,
Freireich EJ:
Characterization of a fusion cDNA (RARA/myl) transcribed from the t(15; 17) translocation breakpoint in acute promyelocytic leukemia.
Mol Cell Biol
12:800,
1992[Abstract/Free Full Text]
293.
Goddard AD,
Borrow J,
Freemont PS,
Solomon E:
Characterization of a zinc finger gene disrupted by the t(15; 17) in acute promyelocytic leukemia.
Science
254:1371,
1991[Abstract/Free Full Text]
294.
Kakizuka A,
Miller WH Jr,
Umesono K,
Warrell RP Jr,
Frankel SR,
Murty VV,
Dmitrovsky E,
Evans RM:
Chromosomal translocation t(15; 17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML.
Cell
66:663,
1991[Medline]
[Order article via Infotrieve]
295.
Alcalay M,
Zangrilli D,
Pandolfi PP,
Longo L,
Mencarelli A,
Giacomucci A,
Rocchi M,
Biondi A,
Rambaldi A,
Lo Coco F:
Translocation breakpoint of acute promyelocytic leukemia lies within the retinoic acid receptor alpha locus.
Proc Natl Acad Sci USA
88:1977,
1991[Abstract/Free Full Text]
296.
Pandolfi PP,
Grignani F,
Alcalay M,
Mencarelli A,
Biondi A,
LoCoco F,
Pelicci PG:
Structure and origin of the acute promyelocytic leukemia myl/RAR alpha cDNA and characterization of its retinoid-binding and transactivation properties.
Oncogene
6:1285,
1991[Medline]
[Order article via Infotrieve]
297.
Perez A,
Kastner P,
Sethi S,
Lutz Y,
Reibel C,
Chambon P:
PMLRAR homodimers Distinct DNA binding properties and heteromeric interactions with RXR.
EMBO J
12:3171,
1993[Medline]
[Order article via Infotrieve]
298.
de The H,
Lavau C,
Marchio A,
Chomienne C,
Degos L,
Dejean A:
The PML-RAR alpha fusion mRNA generated by the t(15; 17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR.
Cell
66:675,
1991[Medline]
[Order article via Infotrieve]
299.
Chen Z,
Brand NJ,
Chen A,
Chen SJ,
Tong JH,
Wang ZY,
Waxman S,
Zelent A:
Fusion between a novel Kruppel-like zinc finger gene and the retinoic acid receptor-alpha locus due to a variant t(11; 17) translocation associated with acute promyelocytic leukaemia.
EMBO J
12:1161,
1993[Medline]
[Order article via Infotrieve]
300.
Redner RL,
Rush EA,
Faas S,
Rudert WA,
Corey SJ:
The t(5; 17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion.
Blood
87:882,
1996[Abstract/Free Full Text]
301.
Guidez F,
Huang W,
Tong JH,
Dubois C,
Balitrand N,
Waxman S,
Michaux JL,
Martiat P,
Degos L,
Chen Z,
Waxman S,
Chomienne C:
Poor response to all-trans retinoic acid therapy in a t(11; 17) PLZF/RAR alpha patient.
Leukemia
8:312,
1994[Medline]
[Order article via Infotrieve]
302.
Licht JD,
Chomienne C,
Goy A,
Chen A,
Scott AA,
Head DR,
Michaux JL,
Wu Y,
DeBlasio A,
Miller WH Jr,
Zelenetz AD,
Willman CL,
Chen Z,
Chen S-J,
Zelent A,
Macintyre E,
Veil A,
Cortes J,
Kantarjian H,
Waxman S:
Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11; 17).
Blood
85:1083,
1995[Abstract/Free Full Text]
303.
Rousselot P,
Hardas B,
Patel A,
Guidez F,
Gaken J,
Castaigne S,
Dejean A,
Dethe H,
Degos L,
Farzaneh F,
Chomienne C:
The PML-Rar alpha gene product of the t(1517) translocation inhibits retinoic acid-induced granulocytic differentiation and mediated transactivation in human myeloid cells.
Oncogene
9:545,
1994[Medline]
[Order article via Infotrieve]
304.
Grignani F,
Ferrucci PF,
Testa U,
Talamo G,
Fagioli M,
Alcalay M,
Mencarelli A,
Peschle C,
Nicoletti I,
Pelicci PG:
The acute promyelocytic leukemia-specific PML-RAR-alpha fusion protein inhibits differentiation and promotes survival of myeloid precursor cells.
Cell
74:423,
1993[Medline]
[Order article via Infotrieve]
305.
Chomienne C,
Balitrand N,
Ballerini P,
Castaigne S,
de The H,
Degos L:
All-trans retinoic acid modulates the retinoic acid receptor-alpha in promyelocytic cells.
J Clin Invest
88:2150,
1991
306.
Leroy P,
Nakshatri H,
Chambon P:
Mouse retinoic acid receptor alpha 2 isoform is transcribed from a promoter that contains a retinoic acid response element.
Proc Natl Acad Sci USA
88:10138,
1991[Abstract/Free Full Text]
307.
Liu M,
Iavarone A,
Freedman LP:
Transcriptional activation of the human p21(WAF1/CIP1) gene by retinoic acid receptor Correlation with retinoid induction of U937 cell differentiation.
J Biol Chem
271:31723,
1996[Abstract/Free Full Text]
308.
Lawrence HJ,
Largman C:
Homeobox genes in normal hematopoiesis and leukemia.
Blood
80:2445,
1992[Free Full Text]
309.
Lowney P,
Corral J,
Detmer K,
LeBeau MM,
Deaven L,
Lawrence HJ,
Largman C:
A human Hox 1 homeobox gene exhibits myeloid-specific expression of alternative transcripts in human hematopoietic cells.
Nucleic Acids Res
19:3443,
1991[Abstract/Free Full Text]
310.
Shen WF,
Largman C,
Lowney P,
Corral JC,
Detmer K,
Hauser CA,
Simonitch TA,
Hack FM,
Lawrence HJ:
Lineage-restricted expression of homeobox-containing genes in human hematopoietic cell lines.
Proc Natl Acad Sci USA
86:8536,
1989[Abstract/Free Full Text]
311.
Magli MC,
Barba P,
Celetti A,
De Vita G,
Cillo C,
Boncinelli E:
Coordinate regulation of HOX genes in human hematopoietic cells.
Proc Natl Acad Sci USA
88:6348,
1991[Abstract/Free Full Text]
312.
Shen WF,
Detmer K,
Mathews CH,
Hack FM,
Morgan DA,
Largman C,
Lawrence HJ:
Modulation of homeobox gene expression alters the phenotype of human hematopoietic cell lines.
EMBO J
11:983,
1992[Medline]
[Order article via Infotrieve]
313.
Lawrence HJ,
Sauvageau G,
Humphries RK,
Largman C:
The role of HOX homeobox genes in normal and leukemic hematopoiesis.
Stem Cells
14:281,
1996[Medline]
[Order article via Infotrieve]
314.
Boylan JF,
Lufkin T,
Achkar CC,
Taneja R,
Chambon P,
Gudas LJ:
Targeted disruption of retinoic acid receptor alpha (RAR alpha) and RAR gamma results in receptor-specific alterations in retinoic acid-mediated differentiation and retinoic acid metabolism.
Mol Cell Biol
15:843,
1995[Abstract]
315.
Liu M,
Lee MH,
Cohen M,
Bommakanti M,
Freedman LP:
Transcriptional activation of the Cdk inhibitor p21 by vitamin D-3 leads to the induced differentiation of the myelomonocytic cell line U937.
Genes Dev
10:142,
1996[Abstract/Free Full Text]
316.
Burn TC,
Petrovick MS,
Hohaus S,
Rollins BJ,
Tenen DG:
Monocyte chemoattractant protein-1 gene is expressed in activated neutrophils and retinoic acid-induced human myeloid cell lines.
Blood
84:2776,
1994[Abstract/Free Full Text]
317.
Kastner P,
Mark M,
Chambon P:
Nonsteroid nuclear receptors: What are genetic studies telling us about their role in real life?
Cell
83:859,
1995[Medline]
[Order article via Infotrieve]
318.
Kastner P,
Grondona JM,
Mark M,
Gansmuller A,
Lemeur M,
Decimo D,
Vonesch JL,
Dolle P,
Chambon P:
Genetic analysis of RXR alpha, developmental function: Convergence of RXR and RAR signaling pathways in heart and eye morphogenesis.
Cell
78:987,
1994[Medline]
[Order article via Infotrieve]
319.
Lohnes D,
Mark M,
Mendelsohn C,
Dolle P,
Dierich A,
Gorry P,
Gansmuller A,
Chambon P:
Function of the retinoic acid receptors (RARs) during development (I). Craniofacial and skeletal abnormalities in RAR double mutants.
Development
120:2723,
1994[Abstract]
320.
Mendelsohn C,
Lohnes D,
Decimo D,
Lufkin T,
Lemeur M,
Chambon P,
Mark M:
Function of the retinoic acid receptors (RARs) during development (II). Multiple abnormalities at various stages of organogenesis in RAR double mutants.
Development
120:2749,
1994[Abstract]
321.
Klug A,
Rhodes D:
Zinc fingers: A novel protein fold for nucleic acid recognition.
Cold Spring Harb Symp Quant Biol
52:473,
1987[Abstract/Free Full Text]
322.
Bogaert T,
Brown N,
Wilcox M:
The Drosophila PS2 antigen is an invertebrate integrin that, like the fibronectin receptor, becomes localized to muscle attachments.
Cell
51:929,
1987[Medline]
[Order article via Infotrieve]
323.
Sukhatme VP:
The Egr transcription factor family: From signal transduction to kidney differentiation.
Kidney Int
41:550,
1992[Medline]
[Order article via Infotrieve]
324.
Gessler M,
Poustka A,
Cavenee W,
Neve RL,
Orkin SH,
Bruns GA:
Homozygous deletion in Wilms' tumours of a zinc-finger gene identified by chromosome jumping.
Nature
343:774,
1990[Medline]
[Order article via Infotrieve]
325.
Call KM,
Glaser T,
Ito CY,
Buckler AJ,
Pelletier J,
Haber DA,
Rose EA,
Kral A,
Yeger H,
Lewis WH,
Jones C,
Housman DE:
Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus.
Cell
60:509,
1990[Medline]
[Order article via Infotrieve]
326.
Gabig TG,
Mantel PL,
Rosli R,
Crean CD:
Requiem: A novel zinc finger gene essential for apoptosis in myeloid cells.
J Biol Chem
269:29515,
1994[Abstract/Free Full Text]
327.
Morishita K,
Parker DS,
Mucenski ML,
Jenkins NA,
Copeland NG,
Ihle JN:
Retroviral activation of a novel gene encoding a zinc finger protein in IL-3-dependent myeloid leukemia cell lines.
Cell
54:831,
1988[Medline]
[Order article via Infotrieve]
328.
Sacchi N,
Nisson PE,
Watkins PC,
Faustinella F,
Wijsman J,
Hagemeijer A:
AMLI fusion transcripts in t(3; 21) positive leukemia: Evidence of molecular heterogeneity and usage of splicing sites frequently involved in the generation of normal AMLI transcripts.
Gene Chromosome Cancer
11:226,
1994[Medline]
[Order article via Infotrieve]
329.
Tanaka T,
Mitani K,
Kurokawa M,
Ogawa S,
Tanaka K,
Nishida J,
Yazaki Y,
Shibata Y,
Hirai H:
Dual functions of the AML1/Evi-1 chimeric protein in the mechanism of leukemogenesis in t(3; 21) leukemias.
Mol Cell Biol
15:2383,
1995[Abstract]
330.
Chen ZX,
Xue YQ,
Zhang R,
Tao RF,
Xia XM,
Li C,
Wang W,
Zu WY,
Yao XZ,
Ling BJ:
A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukemia patients.
Blood
78:1413,
1991[Abstract/Free Full Text]
331.
Reid A,
Gould A,
Brand N,
Cook M,
Strutt P,
Li J,
Licht J,
Waxman S,
Krumlauf R,
Zelent A:
Leukemia translocation gene, PLZF, is expressed with a speckled nuclear pattern in early hematopoietic progenitors.
Blood
86:4544,
1995[Abstract/Free Full Text]
332.
Licht JD,
Shaknovich R,
English MA,
Melnick A,
Li JY,
Reddy JC,
Dong S,
Chen SJ,
Zelent A,
Waxman S:
Reduced and altered DNA-binding and transcriptional properties of the PLZF-retinoic acid receptor-alpha chimera generated in t(11; 17)-associated acute promyelocytic leukemia.
Oncogene
12:323,
1996[Medline]
[Order article via Infotrieve]
333.
Dyck JA,
Maul GG,
Miller WH,
Chen JD,
Kakizuka A,
Evans RM:
A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoproteinn.
Cell
76:333,
1994[Medline]
[Order article via Infotrieve]
334.
Weis K,
Rambaud S,
Lavau C,
Jansen J,
Carvalho T,
Carmofonseca M,
Lamond A,
Dejean A:
Retinoic acid regulates aberrant nuclear localization of PML-RAR alpha in acute promyelocytic leukemia cells.
Cell
76:345,
1994[Medline]
[Order article via Infotrieve]
335.
Koken MH,
Puvion-Dutilleul F,
Guillemin MC,
Viron A,
Linares-Cruz G,
Stuurman N,
de Jong L,
Szostecki C,
Calvo F,
Chomienne C,
Degos L,
Pavion E,
de The H:
The t(15; 17) translocation alters a nuclear body in a retinoic acid-reversible fashion.
EMBO J
13:1073,
1994[Medline]
[Order article via Infotrieve]
336. Li JY, English MA, Bischt S, Waxman S, Licht JD: DNA binding and transcriptional regulation by the promyelocytic zinc finger protein. Blood 84:41a, 1994 (abstr, suppl 1)
337.
Bardwell VJ,
Treisman R:
The POZ domain: A conserved protein-protein interaction motif.
Genes Dev
8:1664,
1994[Abstract/Free Full Text]
338.
Albagli O,
Dhordain P,
Deweindt C,
Lecocq G,
Leprince D:
The BTB/POZ domain: A new protein-protein interaction motif common to DNA- and actin-binding proteins.
Cell Growth Differ
6:1193,
1995[Abstract]
339.
Dong S,
Zhu J,
Reid A,
Strutt P,
Guidez F,
Zhong HJ,
Wang ZY,
Licht J,
Waxman S,
Chomienne C,
Chen Z,
Zelent A,
Chen SJ:
Amino-terminal protein-protein interaction motif (POZ-domain) is responsible for activities of the promyelocytic leukemia zinc finger-retinoic acid receptor-alpha fusion protein.
Proc Natl Acad Sci USA
93:3624,
1996[Abstract/Free Full Text]
340.
Tsai S,
Bartelmez S,
Sitnicka E,
Collins S:
Lymphohematopoietic progenitors immortalized by a retroviral vector harboring a dominant-negative retinoic acid receptor can recapitulate lymphoid, myeloid, and erythroid development.
Genes Dev
8:2831,
1994[Abstract/Free Full Text]
341.
Corey SJ,
Locker J,
Oliveri DR,
Shekhter-Levin S,
Redner RL,
Penchansky L,
Gollin SM:
A non-classical translocation involving 17q12 (retinoic acid receptor alpha) in acute promyelocytic leukemia (APML) with atypical features.
Leukemia
8:1350,
1994[Medline]
[Order article via Infotrieve]
342. Shaknovich R, Yeyati PL, Waxman S, Hellinger N, Nason-Burchenal K, Dmitrovsky E, Strutt P, Zelent AD, Licht JD: The promyelocytic leukemia zinc finger protein (PLZF) suppresses growth and induces apoptosis in the 32DCL3 myeloid cell line. Blood 88:555a, 1996 (abstr, suppl 1)
343.
Mu ZM,
Chin KV,
Liu JH,
Lozano G,
Chang KS:
PML, a growth suppressor disrupted in acute promyelocytic leukemia.
Mol Cell Biol
14:6858,
1994[Abstract/Free Full Text]
344.
Koken MH,
Linares-Cruz G,
Quignon F,
Viron A,
Chelbi-Alix MK,
Sobczak-Thepot J,
Juhlin L,
Degos L,
Calvo F,
de The H:
The PML growth-suppressor has an altered expression in human oncogenesis.
Oncogene
10:1315,
1995[Medline]
[Order article via Infotrieve]
345.
Le XF Yang P,
Chang KS:
Analysis of the growth and transformation suppressor domains of promyelocytic leukemia gene, PML.
J Biol Chem
271:130,
1996[Abstract/Free Full Text]
346.
Hromas R,
Collins SJ,
Hickstein D,
Raskind W,
Deaven LL,
O'Hara P,
Hagen FS,
Kaushansky K:
A retinoic acid-responsive human zinc finger gene, MZF-1, preferentially expressed in myeloid cells.
J Biol Chem
266:14183,
1991
347.
Bavisotto L,
Kaushansky K,
Lin N,
Hromas R:
Antisense oligonucleotides from the stage-specific myeloid zinc finger gene MZF-1 inhibit granulopoiesis in vitro.
J Exp Med
174:1097,
1991
348.
Hoffman SM,
Hromas R,
Amemiya C,
Mohrenweiser HW:
The location of MZF-1 at the telomere of human chromosome 19q makes it vulnerable to degeneration in aging cells.
Leuk Res
20:281,
1996[Medline]
[Order article via Infotrieve]
349.
Vaziri H,
Dragowska W,
Allsopp RC,
Thomas TE,
Harley CB,
Lansdorp PM:
Evidence for a mitotic clock in human hematopoietic stem cells: Loss of telomeric DNA with age.
Proc Natl Acad Sci USA
91:9857,
1994[Abstract/Free Full Text]
350.
Counter CM,
Gupta J,
Harley CB,
Leber B,
Bacchetti S:
Telomerase activity in normal leukocytes and in hematologic malignancies.
Blood
85:2315,
1995[Abstract/Free Full Text]
351.
Morris JF,
Hromas R,
Rauscher FJ:
Characterization of the DNA-binding properties of the myeloid zinc finger protein MZF1: Two independent DNA-binding domains recognize two DNA consensus sequences with a common G-rich core.
Mol Cell Biol
14:1786,
1994[Abstract/Free Full Text]
352.
Morris JF,
Rauscher FJ,
Davis B,
Klemsz M,
Xu D,
Tenen D,
Hromas R:
The myeloid zinc finger gene, MZF-1, regulates the CD34 promoter in vitro.
Blood
86:3640,
1995[Abstract/Free Full Text]
353.
Perrotti D,
Melotti P,
Skorski T,
Casella I,
Peschle C,
Calabretta B:
Overexpression of the zinc finger protein MZF1 inhibits hematopoietic development from embryonic stem cells: Correlation with negative regulation of CD34 and c-myb promoter activity.
Mol Cell Biol
15:6075,
1995[Abstract]
354.
Hromas R,
Morris J,
Cornetta K,
Berebitsky D,
Davidson A,
Sha M,
Sledge G,
Rauscher F:
Aberrant expression of the myeloid zinc finger gene, MZF-1, is oncogenic.
Cancer Res
55:3610,
1995[Abstract/Free Full Text]
355.
Hromas R,
Boswell S,
Shen RN,
Burgess G,
Davidson A,
Cornetta K,
Sutton J,
Robertson K:
Forced over-expression of the myeloid zinc finger gene MZF-1 inhibits apoptosis and promotes oncogenesis in interleukin-3-dependent FDCP.1 cells.
Leukemia
10:1049,
1996[Medline]
[Order article via Infotrieve]
356. Robertson K, Hill D, Ewing C, Srour E, Grigsby S, Hromas R: The myeloid zinc finger gene MZF-1 inhibits retinoic acid-induced apoptosis and CD18 expression in HL60 cells. Blood 86:14a, 1995 (abstr, suppl 1)
357.
Hui P:
Structural and functional characterization of human myeloid zinc finger gene-1 (MZF-1).
Diss Abstr Int
55:2089,
1994
358.
Sukhatme VP:
The Egr family of nuclear signal transducers.
Am J Kidney Dis
17:615,
1991[Medline]
[Order article via Infotrieve]
359.
Bedford FK,
Ashworth A,
Enver T,
Wiedemann LM:
HEX: A novel homeobox gene expressed during haematopoiesis and conserved between mouse and human.
Nucleic Acids Res
21:1245,
1993[Abstract/Free Full Text]
360.
Lee SL,
Wang Y,
Milbrandt J:
Unimpaired macrophage differentiation and activation in mice lacking the zinc finger transactivation factor NGFI-A (EGR1).
Mol Cell Biol
16:4566,
1996[Abstract]
361.
Reddy JC,
Licht JD:
The WT1 Wilms' tumor suppressor gene: how much do we really know?
Biochim Biophys Acta
1287:1,
1996[Medline]
[Order article via Infotrieve]
362.
Rauscher FJ,
Morris JF,
Tournay OE,
Cook DM,
Curran T:
Binding of the Wilms' tumor locus zinc finger protein to the EGR-1 consensus sequence.
Science
250:1259,
1990[Abstract/Free Full Text]
363.
Haber DA,
Park S,
Maheswaran S,
Englert C,
Re GG,
Hazen-Martin DJ,
Sens DA,
Garvin AJ:
WT1-mediated growth suppression of Wilms' tumor cells expressing a WT1 splicing variant.
Science
262:2057,
1993[Abstract/Free Full Text]
364.
Luo XN,
Reddy JC,
Yeyati PL,
Idris AH,
Hosono S,
Haber DA,
Licht JD,
Atweh GF:
The tumor suppressor gene WT1 inhibits ras-mediated transformation.
Oncogene
11:743,
1995[Medline]
[Order article via Infotrieve]
365.
Werner H,
Shen-Orr Z,
Rauscher FJ,
Morris JF,
Roberts CT Jr,
Leroith D:
Inhibition of cellular proliferation by the Wilms' tumor suppressor WT1 is associated with suppression of insulin-like growth factor I receptor gene expression.
Mol Cell Biol
15:3516,
1995[Abstract]
366.
Englert C,
Hou X,
Maheswaran S,
Bennett P,
Ngwu C,
Re GG,
Garvin AJ,
Rosner MR,
Haber DA:
WT1 suppresses synthesis of the epidermal growth factor receptor and induces apoptosis.
EMBO J
14:4662,
1995[Medline]
[Order article via Infotrieve]
367.
Inoue K,
Sugiyama H,
Ogawa H,
Nakagawa M,
Yamagami T,
Miwa H,
Kita K,
Hiraoka A,
Masaoka T,
Nasu K,
Kyo T,
Dohy H,
Nakauchi H,
Ishidate T,
Akiyama T,
Kishimoto T:
WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia.
Blood
84:3071,
1994[Abstract/Free Full Text]
368.
Fraizer GC,
Patmasiriwat P,
Zhang X,
Saunders GF:
Expression of the tumor suppressor gene WT1 in both human and mouse bone marrow.
Blood
86:4704,
1995[Free Full Text]
369.
Phelan SA,
Lindberg C,
Call KM:
Wilms' tumor gene, WT1, mRNA is down-regulated during induction of erythroid and megakaryocytic differentiation of K562 cells.
Cell Growth Differ
5:677,
1994[Abstract]
370.
Sekiya M,
Adachi M,
Hinoda Y,
Imai K,
Yachi A:
Downregulation of Wilms' tumor gene (wt1) during myelomonocytic differentiation in HL60 cells.
Blood
83:1876,
1994[Abstract/Free Full Text]
371.
Kreidberg JA,
Sariola H,
Loring JM,
Maeda M,
Pelletier J,
Housman D,
Jaenisch R:
WT-1 is required for early kidney development.
Cell
74:679,
1993[Medline]
[Order article via Infotrieve]
372.
Miwa H,
Beran M,
Saunders GF:
Expression of the Wilms' tumor gene (WT1) in human leukemias.
Leukemia
6:405,
1992[Medline]
[Order article via Infotrieve]
373.
Hoffman B,
Liebermann DA,
Selvakumaran M,
Nguyen HQ:
Role of c-myc in myeloid differentiation, growth arrest and apoptosis.
Curr Top Microbiol Immunol
211:17,
1996[Medline]
[Order article via Infotrieve]
374.
Brieger J,
Weidmann E,
Fenchel K,
Mitrou PS,
Hoelzer D,
Bergmann L:
The expression of the Wilms' tumor gene in acute myelocytic leukemias as a possible marker for leukemic blast cells.
Leukemia
8:2138,
1994[Medline]
[Order article via Infotrieve]
375.
Algar EM,
Khromykh T,
Smith SI,
Blackburn DM,
Bryson GJ,
Smith PJ:
A WT1 antisense oligonucleotide inhibits proliferation and induces apoptosis in myeloid leukaemia cell lines.
Oncogene
12:1005,
1996[Medline]
[Order article via Infotrieve]
376.
Yamagami T,
Sugiyama H,
Inoue K,
Ogawa H,
Tatekawa T,
Hirata M,
Kudoh T,
Akiyama T,
Murakami A,
Maekawa T:
Growth inhibition of human leukemic cells by WT1 (Wilms' tumor gene) antisense oligodeoxynucleotides: Implications for the involvement of WT1 in leukemogenesis.
Blood
87:2878,
1996[Abstract/Free Full Text]
377.
Pritchard-Jones K,
Renshaw J,
King-Underwood L:
The Wilms tumour (WT1) gene is mutated in a secondary leukaemia in a WAGR patient.
Hum Mol Genet
3:1633,
1994[Abstract/Free Full Text]
378.
Reddy JC,
Morris JC,
Wang J,
English MA,
Haber DA,
Shi Y,
Licht JD:
WT1-mediated transcriptional activation is inhibited by dominant negative mutant proteins.
J Biol Chem
270:10878,
1995[Abstract/Free Full Text]
379.
Englert C,
Vidal M,
Maheswaran S,
Ge Y,
Ezzell RM,
Isselbacher KJ,
Haber DA:
Truncated WT1 mutants alter the subnuclear localization of the wild-type protein.
Proc Natl Acad Sci USA
92:11960,
1995[Abstract/Free Full Text]
380.
Moffett P,
Bruening W,
Nakagama H,
Bardeesy N,
Housman D,
Housman DE,
Pelletier J:
Antagonism of WT1 activity by protein self-association.
Proc Natl Acad Sci USA
92:11105,
1995[Abstract/Free Full Text]
381.
McCann S,
Sullivan J,
Guerra J,
Arcinas M,
Boxer LM:
Repression of the c-myb gene by WT1 protein in T and B cell lines.
J Biol Chem
270:23785,
1995[Abstract/Free Full Text]
382.
Hoffman-Liebermann B,
Liebermann DA:
Suppression of c-myc and c-myb is tightly linked to terminal differentiation induced by IL6 or LIF and not growth inhibition in myeloid leukemia cells.
Oncogene
6:903,
1991[Medline]
[Order article via Infotrieve]
383.
Anfossi G,
Gewirtz AM,
Calabretta B:
An oligomer complementary to c-myb-encoded mRNA inhibits proliferation of human myeloid leukemia cell lines.
Proc Natl Acad Sci USA
86:3379,
1989[Abstract/Free Full Text]
384.
McGinnis W,
Garber RL,
Wirz J,
Kuroiwa A,
Gehring WJ:
A homologous protein-coding sequence in Drosophila homeotic genes and its conservation in other metazoans.
Cell
37:403,
1984[Medline]
[Order article via Infotrieve]
385.
Scott MP,
Weiner AJ:
Structural relationships among genes that control development: Sequence homology between the Antennapedia, Ultrabithorax, and fushi tarazu loci of Drosophila.
Proc Natl Acad Sci USA
81:4115,
1984[Abstract/Free Full Text]
386.
Krumlauf R:
Hox genes in vertebrate development.
Cell
78:191,
1994[Medline]
[Order article via Infotrieve]
387. Zhang P, Benson GV, Rhoades KL, Maas RL, Tenen DG: HoxA-10 deficient mice exhibit increased myelopoiesis and overproliferation of myeloid colony forming units. Proc Natl Acad Sci USA (submitted)
388.
Thorsteinsdottir U,
Sauvageau G,
Hough MR,
Dragowska W,
Lansdorp PM,
Lawrence HJ,
Largman C,
Humphries RK:
Overexpression of HoxA10 in murine hematopoietic cells perturbs both myeloid and lymphoid differentiation and leads to acute myeloid leukemia.
Mol Cell Biol
17:495,
1996[Abstract]
389.
Satokata I,
Benson GV,
Maas RL:
Sexually dimorphic sterility phenotypes in Hoxa10-deficient mice.
Nature
374:460,
1995[Medline]
[Order article via Infotrieve]
390.
Lawrence HJ,
Helgason CD,
Sauvageau G,
Fong S,
Izon D,
Humphries RK,
Largman C:
Mice bearing targeted interruptions of the homeobox gene hoxa9 have defects in myeloid, erythroid, and lymphoid hematopoiesis.
Blood
89:1922,
1997[Abstract/Free Full Text]
391.
Perkins AC,
Cory S:
Conditional immortalization of mouse myelomonocytic, megakaryocytic and mast cell progenitors by the Hox-2.4 homeobox gene.
EMBO J
12:3835,
1993[Medline]
[Order article via Infotrieve]
392.
Perkins A,
Kongsuwan K,
Visvader J,
Adams JM,
Cory S:
Homeobox gene expression plus autocrine growth factor production elicits myeloid leukemia.
Proc Natl Acad Sci USA
87:8398,
1990[Abstract/Free Full Text]
393.
Deguchi Y,
Kirschenbaum A,
Kehrl JH:
A diverged homeobox gene is involved in the proliferation and lineage commitment of human hematopoietic progenitors and highly expressed in acute myelogenous leukemia.
Blood
79:2841,
1992[Abstract/Free Full Text]
394.
Allen JD,
Adams JM:
Enforced expression of Hlx homeobox gene prompts myeloid cell maturation and altered adherence properties of T cells.
Blood
81:3242,
1993[Abstract/Free Full Text]
395.
Lill MC,
Fuller JF,
Herzig R,
Crooks GM,
Gasson JC:
The role of the homeobox gene, HOX B7, in human myelomonocytic differentiation.
Blood
85:692,
1995[Abstract/Free Full Text]
396.
Hromas R,
Radich J,
Collins S:
PCR Cloning of an orphan homeobox gene (PRH) preferentially expressed in myeloid and liver cells.
Biochem Biophys Res Commun
195:976,
1993[Medline]
[Order article via Infotrieve]
397.
Crompton MR,
Bartlett TJ,
Macgregor AD,
Manfioletti G,
Buratti E,
Giancotti V,
Goodwin GH:
Identification of a novel vertebrate homeobox gene expressed in haematopoietic cells.
Nucleic Acids Res
20:5661,
1992[Abstract/Free Full Text]
398.
Manfioletti G,
Gattei V,
Buratti E,
Rustighi A,
De Iuliis A,
Aldinucci D,
Goodwin GH,
Pinto A:
Differential expression of a novel proline-rich homeobox gene (Prh) in human hematolymphopoietic cells.
Blood
85:1237,
1995[Abstract/Free Full Text]
399.
Yu BD,
Hess JL,
Horning SE,
Brown GAJ,
Korsmeyer SJ:
Altered Hox expression and segmental identity in Mll-mutant mice.
Nature
378:505,
1995[Medline]
[Order article via Infotrieve]
400.
Domer PH,
Fakharzadeh SS,
Chen CS,
Jockel J,
Johansen L,
Silverman GA,
Kersey JH,
Korsmeyer SJ:
Acute mixed-lineage leukemia t(4; 11)(q21; q23) generates a MLL-AF4 fusion product.
Proc Natl Acad Sci USA
90:7884,
1993[Abstract/Free Full Text]
401.
Corral J,
Forster A,
Thompson S,
Lampert F,
Kaneko Y,
Slater R,
Kroes WG,
Vanderschoot CE,
Ludwig WD,
Karpas A,
Pocock C,
Cotter F,
Rabbitts TH:
Acute leukemias of different lineages have similar MLL gene fusions encoding related chimeric proteins resulting from chromosomal translocation.
Proc Natl Acad Sci USA
90:8538,
1993[Abstract/Free Full Text]
402.
Chang CP,
Shen WF,
Rozenfeld S,
Lawrence HJ,
Largman C,
Cleary ML:
Pbx proteins display hexapeptide-dependent cooperative DNA binding with a subset of Hox proteins.
Genes Dev
9:663,
1995[Abstract/Free Full Text]
403.
Kamps MP,
Baltimore D:
E2A-Pbx1, the t(1; 19) translocation protein of human pre-B-cell acute lymphocytic leukemia, causes acute myeloid leukemia in mice.
Mol Cell Biol
13:351,
1993[Abstract/Free Full Text]
404.
Luscher B,
Eisenman RN:
New light on Myc and Myb. Part II. Myb.
Genes Dev
4:2235,
1990[Free Full Text]
405.
Golay J,
Basilico L,
Loffarelli L,
Songia S,
Broccoli V,
Introna M:
Regulation of hematopoietic cell proliferation and differentiation by the myb oncogene family of transcription factors.
Int J Clin Lab Res
26:24,
1996[Medline]
[Order article via Infotrieve]
406.
Biedenkapp H,
Borgmeyer U,
Sippel AE,
Klempnauer KH:
Viral myb oncogene encodes a sequence-specific DNA-binding activity.
Nature
335:835,
1988[Medline]
[Order article via Infotrieve]
407.
Melotti P,
Ku D-H,
Calabretta B:
Regulation of the expression of the hematopoietic stem cell antigen CD34: Role of c-myb.
J Exp Med
179:1023,
1994[Abstract/Free Full Text]
408.
Burn TC,
Satterthwaite AB,
Tenen DG:
The human CD34 hematopoietic stem cell antigen promoter and a 3' enhancer direct hematopoietic expression in tissue culture.
Blood
80:3051,
1992[Abstract/Free Full Text]
409.
Krause DS,
Fackler MJ,
Civin CI,
May WS:
CD34: Structure, biology, and clinical utility.
Blood
87:1,
1996[Free Full Text]
410.
Shapiro LH:
Myb and Ets proteins cooperate to transactivate an early myeloid gene.
J Biol Chem
270:8763,
1995[Abstract/Free Full Text]
411.
Burk O,
Mink S,
Ringwald M,
Klempnauer KH:
Synergistic activation of the chicken mim-1 gene by v-myb and C/EBP transcription factors.
EMBO J
12:2027,
1993[Medline]
[Order article via Infotrieve]
412.
Oelgeschlager M,
Janknecht R,
Krieg J,
Schreek S,
Luscher B:
Interaction of the co-activator CBP with Myb proteins: Effects on Myb-specific transactivation and on the cooperativity with NF-M.
EMBO J
15:2771,
1996[Medline]
[Order article via Infotrieve]
413.
Cogswell JP,
Cogswell PC,
Kuehl WM,
Cuddihy AM,
Bender TM,
Engelke U,
Marcu KB,
Ting JPY:
Mechanism of c-myc regulation by c-Myb in different cell lineages.
Mol Cell Biol
13:2858,
1993[Abstract/Free Full Text]
414.
Henriksson M,
Luscher B:
Proteins of the Myc network: Essential regulators of cell growth and differentiation.
Adv Cancer Res
68:109,
1996[Medline]
[Order article via Infotrieve]
415.
Luscher B,
Eisenman RN:
New light on Myc and Myb. Part I. Myc.
Genes Dev
4:2025,
1990[Free Full Text]
416.
Selvakumaran M,
Liebermann D,
Hoffman-Liebermann B:
Myeloblastic leukemia cells conditionally blocked by myc-estrogen receptor chimeric transgenes for terminal differentiation coupled to growth arrest and apoptosis.
Blood
81:2257,
1993[Abstract/Free Full Text]
417.
Ayer DE,
Eisenman RN:
A switch from Myc:Max to Mad:Max heterocomplexes accompanies monocyte/macrophage differentiation.
Genes Dev
7:2110,
1993[Abstract/Free Full Text]
418.
Larsson LG,
Pettersson M,
Oberg F,
Nilsson K,
Luscher B:
Expression of mad, mxi1, max and c-myc During Induced Differentiation of Hematopoietic Cells Opposite regulation of mad and c-myc.
Oncogene
9:1247,
1994[Medline]
[Order article via Infotrieve]
419.
Perkins ND,
Edwards NL,
Duckett CS,
Agranoff AB,
Schmid RM,
Nabel GJ:
A cooperative interaction between NF-kappa-B and Sp1 is required for HIV-1 enhancer activation.
EMBO J
12:3551,
1993[Medline]
[Order article via Infotrieve]
420.
Grove M,
Plumb M:
C/EBP, NF-kappa-B, and c-Ets family members and transcriptional regulation of the cell-specific and inducible macrophage inflammatory protein-1-alpha immediate-early gene.
Mol Cell Biol
13:5276,
1993[Abstract/Free Full Text]
421.
Stein B,
Baldwin AS Jr:
Distinct mechanisms for regulation of the interleukin-8 gene involve synergism and cooperativity between C/EBP and NF-kB.
Mol Cell Biol
13:7191,
1993[Abstract/Free Full Text]
422.
Weih F,
Carrasco D,
Durham SK,
Barton DS,
Rizzo CA,
Ryseck RP,
Lira SA,
Bravo R:
Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-kappa B/Rel family.
Cell
80:331,
1995[Medline]
[Order article via Infotrieve]
423.
Tkachuk DC,
Kohler S,
Cleary ML:
Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias.
Cell
71:691,
1992[Medline]
[Order article via Infotrieve]
424.
Thirman MJ,
Gill HJ,
Burnett RC,
Mbangkollo D,
McCabe NR,
Kobayashi H,
Ziemin-van der Poel S,
Kaneko Y,
Morgan R,
Sandberg AA,
Chaganti RSK,
Larson RA,
LeBeau MM,
Diaz MO,
Rowley JD:
Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 chromosomal translocations.
N Engl J Med
329:909,
1993[Abstract/Free Full Text]
425.
Zeleznik-Le NJ,
Harden AM,
Rowley JD:
11q23 translocations split the "AT-hook" cruciform DNA-binding region and the transcriptional repression domain from the activation domain of the mixed-lineage leukemia (MLL) gene.
Proc Natl Acad Sci USA
91:10610,
1994[Abstract/Free Full Text]
426.
Fidanza V,
Melotti P,
Yano T,
Nakamura T,
Bradley A,
Canaani E,
Calabretta B,
Croce CM:
Double knockout of the ALL-1 gene blocks hematopoietic differentiation in vitro.
Cancer Res
56:1179,
1996[Abstract/Free Full Text]
427.
Mashal R,
Shtalrid M,
Talpaz M,
Kantarjian H,
Smith L,
Beran M,
Cork A,
Trujillo J,
Gutterman J,
Deisseroth A:
Rearrangement and expression of p53 in the chronic phase and blast crisis of chronic myelogenous leukemia.
Blood
75:180,
1990[Abstract/Free Full Text]
428.
Nakai H,
Misawa S,
Toguchida J,
Yandell DW,
Ishizaki K:
Frequent p53 gene mutations in blast crisis of chronic myelogenous leukemia, especially in myeloid crisis harboring loss of a chromosome 17p.
Cancer Res
52:6588,
1992[Abstract/Free Full Text]
429.
Lanza F,
Bi S:
Role of p53 in leukemogenesis of chronic myeloid leukemia.
Stem Cells
13:445,
1995[Medline]
[Order article via Infotrieve]
430.
Zauberman A,
Lupo A,
Oren M:
Identification of p53 target genes through immune selection of genomic DNA: The cyclin G gene contains two distinct p53 binding sites.
Oncogene
10:2361,
1995[Medline]
[Order article via Infotrieve]
431.
Soddu S,
Blandino G,
Citro G,
Scardigli R,
Piaggio G,
Ferber A,
Calabretta B,
Sacchi A:
Wild-type p53 gene expression induces granulocytic differentiation of HL-60 cells.
Blood
83:2230,
1994[Abstract/Free Full Text]
432.
Bohmann D,
Bos TJ,
Admon A,
Nishimura T,
Vogt PK,
Tjian R:
Human proto-oncogene c-jun encodes a DNA binding protein with structural and functional properties of transcription factor AP-1.
Science
238:1386,
1987[Abstract/Free Full Text]
433.
Mollinedo F,
Gajate C,
Tugores A,
Flores I,
Naranjo JR:
Differences in expression of transcription factor AP-1 in human promyelocytic HL-60 cells during differentiation towards macrophages versus granulocytes.
Biochem J
294:137,
1993
434.
Lord KA,
Abdollahi A,
Hoffman-Liebermann B,
Liebermann DA:
Proto-oncogenes of the fos/jun family of transcription factors are positive regulators of myeloid differentiation.
Mol Cell Biol
13:841,
1993[Abstract/Free Full Text]
435.
Salbert G,
Fanjul A,
Piedrafita FJ,
Lu XP,
Kim SJ,
Tran P,
Pfahl M:
Retinoic acid receptors and retinoid-X receptor-alpha down-regulate the transforming growth factor-beta(1) promoter by antagonizing AP-1 activity.
Mol Endocrinol
7:1347,
1993[Abstract/Free Full Text]
436.
Doucas V,
Brockes JP,
Yaniv M,
Dethe H,
Dejean A:
The PML-retinoic acid receptor-alpha translocation converts the receptor from an inhibitor to a retinoic acid-dependent activator of transcription factor-AP-1.
Proc Natl Acad Sci USA
90:9345,
1993[Abstract/Free Full Text]
437.
Satake M,
Nomura S,
Yamaguchpiiwai Y,
Takahama Y,
Hashimot Y,
Niki M,
Kitamura Y,
Ito Y:
Expression of the runt domain-encoding PEBP2 alpha genes in T cells during thymic development.
Mol Cell Biol
15:1662,
1995[Abstract]
438.
Sposi NM,
Zon LI,
Care A,
Valtieri M,
Testa U,
Gabbianelli M,
Mariani G,
Bottero L,
Mather C,
Orkin SH,
Peschle C:
Cell cycle-dependent initiation and lineage-dependent abrogation of GATA-1 expression in pure differentiating hematopoietic progenitors.
Proc Natl Acad Sci USA
89:6353,
1992[Abstract/Free Full Text]
439.
Tsai SF,
Strauss E,
Orkin SH:
Functional analysis and in vivo footprinting implicate the erythroid transcription factor GATA-1 as a positive regulator of its own promoter.
Genes Dev
5:919,
1991[Abstract/Free Full Text]
440.
Zon LI,
Youssoufian H,
Mather C,
Lodish HF,
Orkin SH:
Activation of the erythropoietin receptor promoter by transcription factor GATA-1.
Proc Natl Acad Sci USA
88:10638,
1991[Abstract/Free Full Text]
441.
Visvader J,
Adams JM:
Megakaryocytic differentiation in 416B myeloid cells by GATA-2 and GATA-3 transgenes or 5-azacytidine is tightly coupled to GATA-1 expression.
Blood
82:1493,
1993[Abstract/Free Full Text]
442.
Ihle JN:
Cytokine receptor signalling.
Nature
377:591,
1995[Medline]
[Order article via Infotrieve]
443.
Carlesso N,
Frank DA,
Griffin JD:
Tyrosyl phosphorylation and DNA binding activity of signal transducers and activators of transcription (STAT) proteins in hematopoietic cell lines transformed by Bcr/Abl.
J Exp Med
183:811,
1996[Abstract/Free Full Text]
444.
Tsui HW,
Siminovitch KA,
Desouza L,
Tsui FWL:
Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene.
Nat Genet
4:124,
1993[Medline]
[Order article via Infotrieve]
445.
Shultz LD,
Schweitzer PA,
Rajan TV,
Yi TL,
Ihle JN,
Matthews RJ,
Thomas ML,
Beier DR:
Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene.
Cell
73:1445,
1993[Medline]
[Order article via Infotrieve]
446.
Bollag G,
Clapp DW,
Shih S,
Adler F,
Zhang YY,
Thompson P,
Lange BJ,
Freedman MH,
Mccormick F,
Jacks T,
Shannon K:
Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells.
Nat Genet
12:144,
1996[Medline]
[Order article via Infotrieve]
447.
Largaespada DA,
Brannan CI,
Jenkins NA,
Copeland NG:
Nf1 deficiency causes Ras-mediated granulocyte macrophage colony stimulating factor hypersensitivity and chronic myeloid leukaemia.
Nat Genet
12:137,
1996[Medline]
[Order article via Infotrieve]
448.
Perez C,
Coeffier E,
Moreau-Gachelin F,
Wietzerbin J,
Benech PD:
Involvement of the transcription factor PU.1/Spi-1 in myeloid cell-restricted expression of an interferon-inducible gene encoding the human high-affinity Fc gamma receptor.
Mol Cell Biol
14:5023,
1994[Abstract/Free Full Text]
449.
Feinman R,
Qiu WQ,
Pearse RN,
Nikolajczyk BS,
Sen R,
Sheffery M,
Ravetch JV:
PU.1 and an HLH family member contribute to the myeloid-specific transcription of the Fc-gammaRIIIA promoter.
EMBO J
13:3852,
1994[Medline]
[Order article via Infotrieve]
450.
Rosmarin AG,
Caprio D,
Levy R,
Simkevich C:
CD18 (2 leukocyte integrin) promoter requires PU.1 transcription factor for myeloid activity.
Proc Natl Acad Sci USA
92:801,
1995[Abstract/Free Full Text]
451.
Srikanth S,
Rado TA:
A 30-base pair element is responsible for the myeloid-specific activity of the human neutrophil elastase promoter.
J Biol Chem
269:32626,
1994[Abstract/Free Full Text]
452.
Carvalho M,
Derse D:
The PU.1/Spi-1 proto-oncogene is a transcriptional regulator of a lentivirus promoter.
J Virol
67:3885,
1993[Abstract/Free Full Text]
453.
Maury W:
Monocyte maturation controls expression of equine infectious anemia virus.
J Virol
68:6270,
1994[Abstract/Free Full Text]
454.
Himmelmann A,
Thevenin C,
Harrison K,
Kehrl JH:
Analysis of the Bruton's tyrosine kinase gene promoter reveals critical PU1 and SP1 sites.
Blood
87:1036,
1996[Abstract/Free Full Text]
455. Mitelman F, Heim S: Cancer Cytogentics. New York, NY, Wiley-Liss, 1995, p 69
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
L. M. Starnes, A. Sorrentino, E. Pelosi, M. Ballarino, O. Morsilli, M. Biffoni, S. Santoro, N. Felli, G. Castelli, M. L. De Marchis, et al.
NFI-A directs the fate of hematopoietic progenitors to the erythroid or granulocytic lineage and controls {beta}-globin and G-CSF receptor expression
Blood,
August 27, 2009;
114(9):
1753 - 1763.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-Y. Ahn, K. Seo, O. Weinberg, S. D. Boyd, and D. A. Arber
A Comparison of Two Methods for Screening CEBPA Mutations in Patients with Acute Myeloid Leukemia
J. Mol. Diagn.,
July 1, 2009;
11(4):
319 - 323.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. A. Ho, T. A. Alonzo, R. B. Gerbing, J. Pollard, D. L. Stirewalt, C. Hurwitz, N. A. Heerema, B. Hirsch, S. C. Raimondi, B. Lange, et al.
Prevalence and prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group
Blood,
June 25, 2009;
113(26):
6558 - 6566.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Nowak, D. Stewart, and H. P. Koeffler
Differentiation therapy of leukemia: 3 decades of development
Blood,
April 16, 2009;
113(16):
3655 - 3665.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Laricchia-Robbio, K. Premanand, C. R. Rinaldi, and G. Nucifora
EVI1 Impairs Myelopoiesis by Deregulation of PU.1 Function
Cancer Res.,
February 15, 2009;
69(4):
1633 - 1642.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Koschmieder, B. Halmos, E. Levantini, and D. G. Tenen
Dysregulation of the C/EBP{alpha} Differentiation Pathway in Human Cancer
J. Clin. Oncol.,
February 1, 2009;
27(4):
619 - 628.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Shi, M. Sakuma, T. Mooroka, A. Liscoe, H. Gao, K. J. Croce, A. Sharma, D. Kaplan, D. R. Greaves, Y. Wang, et al.
Down-regulation of the forkhead transcription factor Foxp1 is required for monocyte differentiation and macrophage function
Blood,
December 1, 2008;
112(12):
4699 - 4711.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Gemelli, C. Orlandi, T. Z. Marani, A. Martello, T. Vignudelli, F. Ferrari, M. Montanari, S. Parenti, A. Testa, A. Grande, et al.
The Vitamin D3/Hox-A10 Pathway Supports MafB Function during the Monocyte Differentiation of Human CD34+ Hemopoietic Progenitors
J. Immunol.,
October 15, 2008;
181(8):
5660 - 5672.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Zhang, L.-P. Song, Y. Huang, Q. Zhao, K.-W. Zhao, and G.-Q. Chen
Accumulation of hypoxia-inducible factor-1{alpha} protein and its role in the differentiation of myeloid leukemic cells induced by all-trans retinoic acid
Haematologica,
October 1, 2008;
93(10):
1480 - 1487.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Y. Bertrand, A. D. Kim, S. Teng, and D. Traver
CD41+ cmyb+ precursors colonize the zebrafish pronephros by a novel migration route to initiate adult hematopoiesis
Development,
May 15, 2008;
135(10):
1853 - 1862.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y.-C. Twu, C.-P. Chen, C.-Y. Hsieh, C.-H. Tzeng, C.-F. Sun, S.-H. Wang, M.-S. Chang, and L.-C. Yu
I branching formation in erythroid differentiation is regulated by transcription factor C/EBP{alpha}
Blood,
December 15, 2007;
110(13):
4526 - 4534.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Weigelt, W. Ernst, Y. Walczak, S. Ebert, T. Loenhardt, M. Klug, M. Rehli, B. H. F. Weber, and T. Langmann
Dap12 expression in activated microglia from retinoschisin-deficient retina and its PU.1-dependent promoter regulation
J. Leukoc. Biol.,
December 1, 2007;
82(6):
1564 - 1574.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Y. Bertrand, A. D. Kim, E. P. Violette, D. L. Stachura, J. L. Cisson, and D. Traver
Definitive hematopoiesis initiates through a committed erythromyeloid progenitor in the zebrafish embryo
Development,
December 1, 2007;
134(23):
4147 - 4156.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Yang, L. Wang, T. A. Kalfa, J. A. Cancelas, X. Shang, S. Pushkaran, J. Mo, D. A. Williams, and Y. Zheng
Cdc42 critically regulates the balance between myelopoiesis and erythropoiesis
Blood,
December 1, 2007;
110(12):
3853 - 3861.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Nilsson, P. Eden, E. Olsson, R. Mansson, I. Astrand-Grundstrom, B. Strombeck, K. Theilgaard-Monch, K. Anderson, R. Hast, E. Hellstrom-Lindberg, et al.
The molecular signature of MDS stem cells supports a stem-cell origin of 5q myelodysplastic syndromes
Blood,
October 15, 2007;
110(8):
3005 - 3014.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Lichtinger, R. Ingram, M. Hornef, C. Bonifer, and M. Rehli
Transcription Factor PU.1 Controls Transcription Start Site Positioning and Alternative TLR4 Promoter Usage
J. Biol. Chem.,
September 14, 2007;
282(37):
26874 - 26883.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. S. Chang, R. Santhanam, R. Trotta, P. Neviani, A. M. Eiring, E. Briercheck, M. Ronchetti, D. C. Roy, B. Calabretta, M. A. Caligiuri, et al.
High levels of the BCR/ABL oncoprotein are required for the MAPK-hnRNP-E2 dependent suppression of C/EBP{alpha}-driven myeloid differentiation
Blood,
August 1, 2007;
110(3):
994 - 1003.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T.-H. Pham, S. Langmann, L. Schwarzfischer, C. El Chartouni, M. Lichtinger, M. Klug, S. W. Krause, and M. Rehli
CCAAT Enhancer-binding Protein beta Regulates Constitutive Gene Expression during Late Stages of Monocyte to Macrophage Differentiation
J. Biol. Chem.,
July 27, 2007;
282(30):
21924 - 21933.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. T. Sasmono, A. Ehrnsperger, S. L. Cronau, T. Ravasi, R. Kandane, M. J. Hickey, A. D. Cook, S. R. Himes, J. A. Hamilton, and D. A. Hume
Mouse neutrophilic granulocytes express mRNA encoding the macrophage colony-stimulating factor receptor (CSF-1R) as well as many other macrophage-specific transcripts and can transdifferentiate into macrophages in vitro in response to CSF-1
J. Leukoc. Biol.,
July 1, 2007;
82(1):
111 - 123.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Resende, G. Regalo, C. Duraes, F. Carneiro, and J. C. Machado
Genetic Changes of CEBPA in Cancer: Mutations or Polymorphisms?
J. Clin. Oncol.,
June 10, 2007;
25(17):
2493 - 2494.
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Fazi, G. Zardo, V. Gelmetti, L. Travaglini, A. Ciolfi, L. Di Croce, A. Rosa, I. Bozzoni, F. Grignani, F. Lo-Coco, et al.
Heterochromatic gene repression of the retinoic acid pathway in acute myeloid leukemia
Blood,
May 15, 2007;
109(10):
4432 - 4440.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Agrawal, W.-K. Hofmann, N. Tidow, M. Ehrich, D. v. d. Boom, S. Koschmieder, W. E. Berdel, H. Serve, and C. Muller-Tidow
The C/EBP{delta} tumor suppressor is silenced by hypermethylation in acute myeloid leukemia
Blood,
May 1, 2007;
109(9):
3895 - 3905.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-i. Machiya, Y. Shibata, K. Yamauchi, N. Hirama, T. Wada, S. Inoue, S. Abe, N. Takabatake, M. Sata, and I. Kubota
Enhanced Expression of MafB Inhibits Macrophage Apoptosis Induced by Cigarette Smoke Exposure
Am. J. Respir. Cell Mol. Biol.,
April 1, 2007;
36(4):
418 - 426.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Starkova, J. Madzo, G. Cario, T. Kalina, A. Ford, M. Zaliova, O. Hrusak, and J. Trka
The Identification of (ETV6)/RUNX1-Regulated Genes in Lymphopoiesis Using Histone Deacetylase Inhibitors in ETV6/RUNX1-Positive Lymphoid Leukemic Cells
Clin. Cancer Res.,
March 15, 2007;
13(6):
1726 - 1735.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. H. Carter and W. G. Tourtellotte
Early Growth Response Transcriptional Regulators Are Dispensable for Macrophage Differentiation
J. Immunol.,
March 1, 2007;
178(5):
3038 - 3047.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Iwasaki, S.-i. Mizuno, Y. Arinobu, H. Ozawa, Y. Mori, H. Shigematsu, K. Takatsu, D. G. Tenen, and K. Akashi
The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages.
Genes & Dev.,
November 1, 2006;
20(21):
3010 - 3021.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Ricote, C. S. Snyder, H.-Y. Leung, J. Chen, K. R. Chien, and C. K. Glass
Normal hematopoiesis after conditional targeting of RXR{alpha} in murine hematopoietic stem/progenitor cells
J. Leukoc. Biol.,
October 1, 2006;
80(4):
850 - 861.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Li, J.-W. Xiong, C. S. Shelley, H. Park, and M. A. Arnaout
The transcription factor ZBP-89 controls generation of the hematopoietic lineage in zebrafish and mouse embryonic stem cells
Development,
September 15, 2006;
133(18):
3641 - 3650.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Cimino, F. Lo-Coco, S. Fenu, L. Travaglini, E. Finolezzi, M. Mancini, M. Nanni, A. Careddu, F. Fazi, F. Padula, et al.
Sequential Valproic Acid/All-trans Retinoic Acid Treatment Reprograms Differentiation in Refractory and High-Risk Acute Myeloid Leukemia.
Cancer Res.,
September 1, 2006;
66(17):
8903 - 8911.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Yaneva, S. Kippenberger, N. Wang, Q. Su, M. McGarvey, A. Nazarian, L. Lacomis, H. Erdjument-Bromage, and P. Tempst
PU.1 and a TTTAAA Element in the Myeloid Defensin-1 Promoter Create an Operational TATA Box That Can Impose Cell Specificity onto TFIID Function.
J. Immunol.,
June 1, 2006;
176(11):
6906 - 6917.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. U. Mueller, T. Pabst, J. Fos, V. Petkovic, M. F. Fey, N. Asou, U. Buergi, and D. G. Tenen
ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression
Blood,
April 15, 2006;
107(8):
3330 - 3338.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Nishida, N. Hosen, T. Shirakata, K. Kanato, M. Yanagihara, S.-i. Nakatsuka, Y. Hoshida, T. Nakazawa, Y. Harada, N. Tatsumi, et al.
AML1-ETO rapidly induces acute myeloblastic leukemia in cooperation with the Wilms tumor gene, WT1
Blood,
April 15, 2006;
107(8):
3303 - 3312.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Grisaru, M. Pick, C. Perry, E. H. Sklan, R. Almog, I. Goldberg, E. Naparstek, J. B. Lessing, H. Soreq, and V. Deutsch
Hydrolytic and Nonenzymatic Functions of Acetylcholinesterase Comodulate Hemopoietic Stress Responses
J. Immunol.,
January 1, 2006;
176(1):
27 - 35.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. F. Peterson, A. Boyapati, V. Ranganathan, A. Iwama, D. G. Tenen, S. Tsai, and D.-E. Zhang
The Hematopoietic Transcription Factor AML1 (RUNX1) Is Negatively Regulated by the Cell Cycle Protein Cyclin D3
Mol. Cell. Biol.,
December 1, 2005;
25(23):
10205 - 10219.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Yu, X. Zhu, W. Pi, J. Ling, L. Ko, Y. Takeda, and D. Tuan
The Long Terminal Repeat (LTR) of ERV-9 Human Endogenous Retrovirus Binds to NF-Y in the Assembly of an Active LTR Enhancer Complex NF-Y/MZF1/GATA-2
J. Biol. Chem.,
October 21, 2005;
280(42):
35184 - 35194.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Shimokawa and C. Ra
C/EBP{alpha} functionally and physically interacts with GABP to activate the human myeloid IgA Fc receptor (Fc{alpha}R, CD89) gene promoter
Blood,
October 1, 2005;
106(7):
2534 - 2542.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Tamura, P. Thotakura, T. S. Tanaka, M. S. H. Ko, and K. Ozato
Identification of target genes and a unique cis element regulated by IRF-8 in developing macrophages
Blood,
September 15, 2005;
106(6):
1938 - 1947.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Rosenbauer, S. Koschmieder, U. Steidl, and D. G. Tenen
Effect of transcription-factor concentrations on leukemic stem cells
Blood,
September 1, 2005;
106(5):
1519 - 1524.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Iwasaki, C. Somoza, H. Shigematsu, E. A. Duprez, J. Iwasaki-Arai, S.-i. Mizuno, Y. Arinobu, K. Geary, P. Zhang, T. Dayaram, et al.
Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation
Blood,
September 1, 2005;
106(5):
1590 - 1600.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Goffin, D. Demonte, C. Vanhulle, S. de Walque, Y. de Launoit, A. Burny, Y. Collette, and C. Van Lint
Transcription factor binding sites in the pol gene intragenic regulatory region of HIV-1 are important for virus infectivity
Nucleic Acids Res.,
August 1, 2005;
33(13):
4285 - 4310.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. T. Porse, D. Bryder, K. Theilgaard-Monch, M. S. Hasemann, K. Anderson, I. Damgaard, S. E. W. Jacobsen, and C. Nerlov
Loss of C/EBP{alpha} cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage
J. Exp. Med.,
July 5, 2005;
202(1):
85 - 96.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. P. Whitman, S. Liu, T. Vukosavljevic, L. J. Rush, L. Yu, C. Liu, M. I. Klisovic, K. Maharry, M. Guimond, M. P. Strout, et al.
The MLL partial tandem duplication: evidence for recessive gain-of-function in acute myeloid leukemia identifies a novel patient subgroup for molecular-targeted therapy
Blood,
July 1, 2005;
106(1):
345 - 352.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Leeanansaksiri, H. Wang, J. M. Gooya, K. Renn, M. Abshari, S. Tsai, and J. R. Keller
IL-3 Induces Inhibitor of DNA-Binding Protein-1 in Hemopoietic Progenitor Cells and Promotes Myeloid Cell Development
J. Immunol.,
June 1, 2005;
174(11):
7014 - 7021.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Okuno, G. Huang, F. Rosenbauer, E. K. Evans, H. S. Radomska, H. Iwasaki, K. Akashi, F. Moreau-Gachelin, Y. Li, P. Zhang, et al.
Potential Autoregulation of Transcription Factor PU.1 by an Upstream Regulatory Element
Mol. Cell. Biol.,
April 1, 2005;
25(7):
2832 - 2845.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Introduction
Methods
Introduction