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Blood, Vol. 94 No. 2 (July 15), 1999: pp. 417-428

REVIEW ARTICLE

Chromatin Remodeling and Leukemia: New Therapeutic Paradigms

By Robert L. Redner, Jianxiang Wang, and Johnson M. Liu

From the Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA; and the Hematology Branch, National Heart, Lung and Blood Institute, Bethesda MD.


    INTRODUCTION
TOP
INTRODUCTION
CHROMATIN: BEADS ON A...
NUCLEOSOMAL REMODELING
DISRUPTION OF CHROMATIN...
CHROMATIN THERAPY
REFERENCES

LOCAL REMODELING OF chromatin is a key step in the transcriptional activation of genes. Dynamic changes in the nucleosomal packaging of DNA must occur to allow transcriptional proteins contact with the DNA template. The realization that the proteins that regulate the modification of chromatin are themselves disrupted in many leukemic chromosomal rearrangements has generated new excitement in the study of chromatin structure. Recent reports have kindled the hope that pharmacological manipulation of chromatin remodeling might develop into a potent and specific strategy for the treatment of these leukemias. In this review, we will discuss the structure of chromatin and the mechanisms by which cells remodel chromatin, alteration of these pathways in leukemias, and therapeutic approaches.


    CHROMATIN: BEADS ON A STRING OR STRING ON BEADS?
TOP
INTRODUCTION
CHROMATIN: BEADS ON A...
NUCLEOSOMAL REMODELING
DISRUPTION OF CHROMATIN...
CHROMATIN THERAPY
REFERENCES

The condensation of DNA into an ordered chromatin structure allows the cell to solve the topological problems associated with storing huge molecules of chromosomal DNA within the nucleus. DNA is packaged into chromatin in orderly repeating protein-DNA complexes called nucleosomes.1,2 Each nucleosome consists of approximately 146 bp of double-stranded DNA wrapped 1.8 times around a core of 8 histone molecules (Fig 1). Two molecules each of H2A, H2B, H3, and H4 comprise the histone ramp around which the DNA superhelix winds. Stretches of DNA up to 100 bp separate adjacent nucleosomes. Multiple nuclear proteins bind to this linker region, some of which may be responsible for the ordered wrapping of strings of nucleosomes into higher-order chromatin structures.3,4


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  		Fig 1. Cartoon of nucleosomal structure. (A) represents the random-coiled tails of the histone octamer intertwined with DNA. (B) represents the nucleosome with histones acetylated (acetyl groups drawn as lollipop structures). The acetylated histone tails do not bind the DNA strands. This allows the DNA to assume a more open configuration that is accessible to the transcriptional machinery.

Nucleosomal structure has been well characterized by x-ray crystallographic studies, most recently to a resolution of 2.8 Å.1 The histones are arranged as heterodimers of H2A and H2B, H3 and H4; the heterodimers, in turn, form a tetrameric structure known as the octamer core. Each histone heterodimer binds approximately 30 bp of DNA through electrostatic contacts with the phosphate backbone in the minor groove of the DNA. The interaction with histones causes the DNA to become distorted and bend and bulge at several positions: this twisting of the helix results in a deviation of the periodicity of the basepairs as they spiral along the DNA superhelix. The change in periodicity leads to alignment of the DNA minor grooves to form channels, through which pass the random-coil histone tails. The histone tails are thus able to contact the DNA on the exterior of the nucleosomal particle to further stabilize DNA/histone interactions.

Although nucleosomal architecture depends primarily on nonspecific interactions between histones and the phosphate backbone of DNA, the thermodynamic stability of the interaction is influenced by the basepair composition of the DNA. A-T-rich sequences in particular impart the DNA with flexibility that allows it to form the tertiary structures necessary for optimal nucleosomal packing.1,5 In addition, histone leucine residues bound to the minor groove of DNA are able to interact with nearby thymidine residues; arginines form hydrogen bonds with neighboring pyrimidines. These sequence-specific characteristics likely contribute to variations in the number of bases in each nucleosome particle, the length of internucleosomal spacer DNA, and the phasing of adjacent nucleosomes.


    NUCLEOSOMAL REMODELING
TOP
INTRODUCTION
CHROMATIN: BEADS ON A...
NUCLEOSOMAL REMODELING
DISRUPTION OF CHROMATIN...
CHROMATIN THERAPY
REFERENCES

Both distortion of the periodicity of the superhelix and electrostatic shielding by the positively charged histones act to constrain the access of nonhistone proteins to nucleosomal DNA.6,7 Extensive remodeling of chromatin structure, particularly at cis-acting promoter sites necessary for transcriptional initiation, must take place for the DNA template to become accessible to the transcriptional machinery. A complete picture of the way in which DNA separates from nucleosomes during transcription is not yet available, but most likely only partial dissociation from the core histones is necessary.8

Several mechanisms have been identified that contribute to chromatin remodeling. They vary from those that alter histone-DNA interaction to those that physically dissociate the DNA from histones in an ATP-dependent manner to those that destabilize histone-histone tetramerization (see the recent review by Tsukiyama and Wu9 for a more detailed discussion). All of these processes likely act simultaneously and in concert to regulate access to the DNA template. Two of the mechanisms are particularly relevant to the discussion of leukemic fusion proteins (see below): histone acetylation and ATPase-mediated DNA-histone dissociation.

The best understood mechanism by which cells regulate chromatin structure is posttranslational modification of histones by acetylation.10-15 Change in electrostatic attraction for DNA and steric hindrance introduced by the hydrophobic acetyl group leads to destabilization of the interaction of histones with DNA.1,11-13,15,16 Lysine residues in the N-terminal extensions of H2B, H3, and H4 that bind to the exterior surface of nucleosomes are particularly accessible to acetylation. Acetylation of residues within the octamer core interferes with formation of the histone heterodimers and tetramers around which the DNA winds. Furthermore, posttranslational modification of histones interferes with interactions with nonhistone, chromatin-associated proteins, such as MeCP2 (which binds to methylated regions of DNA17) and the high-mobility group proteins (HMG,18,19 so named for their properties in electrophoretic fields), which also contribute to higher-order nucleosomal packing. In summary, acetylation of histones disrupts nucleosomes and allows the DNA to become accessible to transcriptional machinery. Removal of the acetyl groups allows the histones to bind more tightly to DNA and to maintain a transcriptionally repressed chromatin architecture. Acetylation is mediated by a series of enzymes with histone acetylase (histone acetyl transferase [HAT]) activity; conversely, acetyl groups are removed by specific histone deacetylase (HDAC) enzymes.

The ability to modulate histone acetylation in a gene-specific fashion presents a challenge for cells. The state of histone acetylation is determined by the balance between competing enzymatic activities of histone acetyltransferases and deacetylases. Fine regulation of the catalytic activities of these enzymes likely involves cooperative subunit interaction and posttranslational modification. However, our limited understanding of the regulation of gene-specific histone acetylation is best captured in the rather simplistic model of local recruitment of acetylases or deacetylases by sequence-specific DNA binding proteins.

The paradigm for local remodeling of chromatin through gene-specific recruitment of HAT activity is the retinoic acid receptor (RAR).20 Because RAR-mediated chromatin remodeling is perturbed in acute promyelocytic leukemia (APL; see below), it is appropriate to consider this model in some depth; similar models have been developed for other transcriptional activators and repressors.21 RAR is a ligand-dependent transcriptional activator.22 Through its zinc (Zn) finger domain, it binds as a heterodimer with a related protein, RXR,23 to a well-defined consensus DNA sequence found in the promoters of retinoic acid-responsive genes.24 In the absence of ligand (retinoic acid [RA]), the RXR/RAR heterodimer binds to DNA and actively represses transcription below the basal level expected from random initiation by the transcriptional machinery.25a It does this through an indirect mechanism. The RXR/RAR heterodimer binds a nuclear corepressor molecule, either N-CoR26,27 (Nuclear Receptor Co-Repressor) or SMRT28,29 (Silencing Mediator of Retinoid and Thyroid Receptors), through specific interaction domains in the ligand-binding region of RAR. N-CoR, the better analyzed of the 2, binds to many sequence-specific DNA-binding transcriptional repressor proteins (Table 1). N-CoR (or SMRT) itself binds another intermediary protein, Sin3, which serves as a bridge to HDAC1, a histone deacetylase30-32 (there have been 3 homologous HDACs identified in human cells33). Thus, the end result of the association of unliganded RAR/RXR with N-CoR is to recruit HDAC1 to the local environment of the promoter. By removing acetyl groups from histones and restructuring the chromatin into a repressive configuration, HDAC1 serves as the effector molecule in this pathway. N-CoR, Sin3, and HDAC1 function in many repressive pathways, including transcriptional silencing by the MAD/MAX members of the MYC family,30,31,34,35 ETO36-38 (see below), and other members of the steroid hormone receptor superfamily.26,32

                              
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  		Table 1. Corepressor Proteins

Binding of ligand to RAR initiates a conformational change in the C-terminus of RAR, which contains the N-CoR binding site.39-41 An amphipathic helix within RAR (helix 12, which is highly conserved within the steroid receptor superfamily) swings into a position that both locks the ligand into its binding pocket and creates a new hydrophobic domain. N-CoR does not bind to this altered conformation of RAR, and hence the N-CoR/Sin3/HDAC1 complex dissociates itself from liganded RAR. In its place, the newly created hydrophobic domain within RAR binds a large multimolecular complex that enhances transcriptional activation.21,42,43 Several components of this coactivator complex have been identified (Table 2), including the adenovirus E1A-associated protein p300, pCAF (CBP-associated factor44), and a family of homologous 160-kD proteins, including p/CIP (p300/CBP cointegrator-associated protein),43,45 NCoA-146 (nuclear coactivator-1, also known as SRC-142), and NCoA-2 (also known as TIF-246-48). p300, or the homologous cyclic-AMP response-element-binding protein cofactor CBP,21,43,49,50 has been shown to interact through nonoverlapping domains with at least a dozen DNA-binding transcriptional activators, including other members of the steroid hormone receptor family, members of the STAT family, Jun, Fos, AML1, and Myb (see review by Giles et al51). In this regard, p300/CBP serves as a bridge between multiple transcriptional activators. Several members of this complex have HAT activity, including pCAF,44,52 the 160-kD proteins,53 and p300/CBP itself.50 Thus, recruitment of the coactivator complex brings several histone acetylases to the proximity of the promoter to which RAR binds, so that the deacetylated histones can be efficiently acetylated. The coactivator complex serves to reverse the suppressive effects of the N-CoR/Sin3/HDAC1 complex and, by decreasing the affinity of histones for DNA, remodel nucleosomal configuration so that the DNA template can be accessed for transcription. It is as yet unclear which of the proteins in the complex directly interact with histones, which acetylate other proteins in the complex (or the proteins that comprise the basal transcriptional machinery), which stabilize the nascent basal transcriptional machinery or, which, as has been proposed for p300/CBP, function in all 3 capacities.50

                              
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  		Table 2. Histone Acetylases

An interesting twist to this paradigm has recently arisen through studies of DNA methylation, which has been a long-accepted mechanism of transcriptional suppression54,55. A possible contributor to the transcriptional-silencing effect of DNA-methylation may be the MeCP family of proteins, which specifically bind to regions of methylated DNA between adjacent nucleosomes.56 The MeCP2 protein directly binds Sin3/HDAC1.17 Thus, by recruiting a histone deacetylase, MeCP2-binding leads to a change in the state of histone acetylation and in the chromatin structure of methylated DNA. Whether this mechanism directly mediates the transcriptional silencing effects of DNA methylation or whether it serves a synergistic or supporting role is not yet clear. However, it leads to the interesting speculation that DNA-methyltransferase inhibitors such as 5-azacytidine57 might alter transcriptional activity by indirectly remodeling regions of methylated chromatin.

A second mechanism for alteration of chromatin that is less well understood than acetylation of histones involves an ATP-dependent enzymatic activity that directly acts on nucleosomal structure. Based on analogous protein complexes in yeast and Drosophila (known by the acronyms SWI/SNF,58-62 NURF,63 and RSC64,65), it has been proposed that these complexes act as ATP-dependent motors that track along the DNA strands and pull them away from the histone octamer cores.59-62,66 During this shift of histone-DNA contact points, the DNA would presumably become accessible to the transcriptional machinery. However, there is conflicting evidence to suggest that these complexes serve to maintain chromatin in a repressive configuration, perhaps through dissociating other chromatin-associated proteins from the DNA, such as errant TATA-binding protein.67 Reinforcing the concept of interplay between the chromatin remodeling mechanisms is the finding that 2 members of the human p300-associated coactivator complex68,69 have the predicted ATPase activities requisite for a SWI/SNF type of engine.


    DISRUPTION OF CHROMATIN REMODELING MECHANISMS IN LEUKEMIA
TOP
INTRODUCTION
CHROMATIN: BEADS ON A...
NUCLEOSOMAL REMODELING
DISRUPTION OF CHROMATIN...
CHROMATIN THERAPY
REFERENCES

APL: Abnormal histone deacetylation.   Chromatin remodeling is fundamental to transcription. The models presented above outline the normal control of chromatin remodeling during gene-specific transcription. Disruption of these mechanisms gives rise to transcriptional chaos and leukemic transformation. The best understood example of this is in APL (French-American-British [FAB] M3).

APL holds a unique position in the study of leukemias in that it is the only form of leukemia and the only malignancy described to date that responds to differentiation therapy. First published in Blood by Huang et al70 from the Shanghai Institute of Hematology, APL blasts undergo terminal differentiation in response to all-trans retinoic acid (ATRA). Differentiation therapy with ATRA has become the mainstay of therapy for this disease.71,72 Although relapses uniformly occur when used by itself, in combination with conventional chemotherapy, ATRA has revolutionized the treatment of APL, generating response rates of close to 90%, with 3-year disease-free survival greater than 75%.73

The explanation for the restriction of the success of ATRA therapy to the M3 subtype of leukemias likely lies in the chromatin alterations induced by the RAR-fusion proteins expressed uniquely in APL cells (Fig 2). RARalpha (there are 3 homologous RAR proteins, called alpha , beta , and gamma ) is a transcriptional activator that binds to specific DNA sequences and inducibly recruits corepressor or coactivator complexes to regulate transcription of retinoic acid-responsive genes (see above). Ordered expression of retinoic acid-responsive genes is necessary for myeloid development; dominant-negative mutants of RARalpha inhibit myeloid maturation at the promyelocytic stage.74,75 All patients with APL have a chromosomal translocation within the second intron of the RARalpha locus on chromosome 17q12 to produce a chimeric protein comprised of all but the first 30 AA of RARalpha .76 The N-terminal fusion partners are PML77,78 on chromosome 15q21, PLZF79 on chromosome 11q23, NPM80 on chromosome 5q31, or NUMA81 on chromosome 11q13. The PML-fusion is the most common: only 8 patients with PLZF-RARalpha ,82 3 with NPM-RARalpha ,80 and 1 with NUMA-RARalpha 81 have been described to date. All of these RARalpha fusion proteins contain the DNA-binding, heterodimerization, ligand-binding, corepressor-binding, and coactivator-binding motifs of RARalpha . Like wild-type RARalpha , they bind to retinoic acid-response elements in DNA and, under appropriate conditions, can activate transcription of RA-target genes.77,80,83,84


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  		Fig 2. Fusion proteins in acute promyelocytic leukemia. (A) indicates the unliganded interactions of the RXR/RARalpha heterodimer with an N-CoR/Sin3/HDAC1 complex. Upon binding retinoid acid, the RXR/RARalpha heterodimer releases the corepressor complex and binds a coactivator complex with histone acetylase activity. (B) indicates the analogous interactions of the RXR/PML-RARalpha heterodimer with the corepressor complex. Release of the corepressor complex occurs only in the presence of pharmacological levels of retinoic acid. (C) depicts the ligand-independent binding of the corepressor complex to PLZF-RARalpha . (It has been proposed, but not yet been formally demonstrated, that liganded RXR/PLZF-RARalpha binds both coactivator and corepressor complexes.) Chromatin remodeling occurs only in the presence of both RA and an HDAC inhibitor.



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  		Fig 3. AML-ETO fusion protein. (A) depicts the association of the AML1 transcriptional activator with a coactivator complex; (B) indicates the binding of a corepressor to the AML-ETO fusion protein.



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  		Fig 4. MLL-CBP. One of several models for MLL-CBP function. (A) MLL binds to DNA through interactions between its AT hooks and the minor groove of DNA. (B) MLL-CBP alters chromatin structure at MLL-target sites through the action of the histone acetyltransferase domain of CBP.

However, at physiological levels of retinoic acid, PML-RARalpha represses rather than activates transcription.85-88 This is apparently the consequence of enhanced interaction between PML-RARalpha and the N-CoR/Sin3/HDAC1 corepressor complex. PML-RARalpha binds N-CoR at levels of ligand that are otherwise sufficient to release the corepressor complex from wild-type RARalpha . By maintaining the promoters of RA-responsive genes in a repressive deacetylated configuration, PML-RARalpha suppresses transcription and produces the identical phenotype to that experimentally produced by a dominant-negative inhibitor of RARalpha .74 Only at pharmacological levels of ligand does PML-RARalpha release N-CoR, recruit a coactivator complex, and allow histone acetylation and chromatin remodeling to proceed. Thus, for PML-RARalpha -expressing APL cells, pharmacological levels of RA are needed to induce differentiation.

If the end result of PML-RARalpha binding to the corepressor complex is active repression of transcription through a HDAC1-dependent pathway, then one would predict that the APL phenotype might be overcome by inhibitors of HDAC. This prediction has been validated by the finding that RA and inhibitors of HDAC1 (see below) synergize to induce differentiation of the APL cell line, NB4, or U937 cells engineered to express PML-RARalpha .85-87 The molecular mechanism underlying the strong interaction of PML-RARalpha with N-CoR is not yet known: there is apparently no direct binding between PML and N-CoR. Fusion with PML presumably inhibits the ligand-induced conformational changes necessary for release of the N-CoR complex. A similar mechanism may also be at play with the NPM-RARalpha t(5;17) fusion, which is also retinoic acid-responsive.89

The t(11;17)(q23;q12) chromosomal translocation of APL fuses the same sequences of RARalpha to the N-terminus of PLZF.79 PLZF is itself a DNA-binding transcription factor, capable of binding N-CoR via the 120 AA N-terminal POZ motif90, 91 (conserved between poxvirus and zinc finger proteins) retained in the PLZF-RARalpha fusion.92-94 As a result, PLZF-RARalpha interacts with N-CoR through 2 binding sites: a ligand-dependent site in the RARalpha domain and a ligand-independent site in the PLZF N-terminus.85-88,93 When retinoic acid binds to the ligand-binding domain of PLZF-RARalpha , the RARalpha domain of the fusion protein loses its attraction for N-CoR, but the PLZF ligand-independent domain continues to bind N-CoR. As a result, even in the presence of pharmacological levels of retinoic acid, N-CoR/Sin3/HDAC1 remains tethered to RA-responsive promoters, permanently suppressing transcription and blocking differentiation. This model explains the lack of response of t(11;17) patients to ATRA differentiation therapy95 and may explain in part the observation that t(11;17) blasts show morphologic features indicating less differentiation than classical APL cells.82 Based on this model, one would predict that inhibitors of HDAC might partially overcome the suppressive effects of PLZF-RARalpha . This is indeed the case: several groups have recently demonstrated that inhibitors of HDAC1 synergize with retinoic acid to induce differentiation of otherwise nonresponsive PLZF-RARalpha cells.85-88

AML1-ETO: Exchanging a coactivator for a corepressor.   The AML1-ETO oncoprotein has recently been shown to alter gene expression through an analogous mechanism of errant recruitment of an N-CoR repressor complex. AML1-ETO is derived from the fusion of the AML1 gene on chromosome 21q22 with the ETO (also called MTG8) locus on chromosome 8q22 (see review by Hiebert et al96). Accounting for over 10% of acute myeloid leukemias (AML), t(8;21) is seen exclusively in FAB M2. Patients with t(8;21) have a better response rate to chemotherapy and a higher remission rate than M2 patients with normal karyotype.97,98

AML1 is a sequence-specific DNA binding protein that complexes with core binding factor beta  (CBFbeta ) to activate transcription of target genes.99 Many of the AML1-dependent genes have been implicated in myeloid maturation, including interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), myeloperoxidase, and neutrophil elastase.96 Unlike the RARalpha model discussed in detail above, AML1/CBFbeta binds no ligand; regulation of AML1 activity occurs as a result of transcriptional and posttranslational modulation of AML1 (as yet, these mechanisms have been poorly defined). Recently, it has been shown that the C-terminus of AML1 interacts with a p300-containing coactivator complex,100 suggesting that one of the mechanisms by which AML1 activates transcription is through local histone acetylation and nucleosomal remodeling.

AML1-ETO, on the other hand, inhibits transcription of AML1-responsive genes.99,101 AML1-ETO knock-in mice102 have similar embryonic-lethal phenotype as aml1 knock-out mice,25 which show absent fetal liver hematopoiesis. The AML1-ETO protein contains the N-terminal 177 AA of AML1, including the runt homology domain that mediates sequence-specific DNA binding,99 fused to near full-length ETO protein.103 ETO was originally identified through its involvement in the t(8;21) translocation. Expressed in CD34 cells and in the brain,104 ETO shares regions of homology with the Drosophila Nervy protein.103 It contains 2 putative C-terminal Zn-finger domains, but has not yet been shown to directly interact with DNA. Little is known about its normal function. It acts as a transforming oncogene when overexpressed in NIH3T3 cells.105 In tests of its ability to modulate transcription, ETO acts as a repressor, although it is not yet clear how this relates to the function of wild-type ETO.36

Recently, our group demonstrated that ETO's ability to repress transcription is mediated through its interaction with N-CoR and recruitment of an N-CoR/Sin3/HDAC1 complex.36 These results have been confirmed by 2 other laboratories.37,38 Because the N-CoR interaction domain maps to the Zn-finger regions of ETO, a region that is retained in the AML1-ETO fusion, the same domain likely mediates AML1-ETO's repressive effects. AML1-ETO mutants that lack this domain lose their ability to recruit N-CoR and lose their ability to repress transcription and inhibit differentiation.36,38 The model that has developed is the following (Fig 3): AML1-ETO binds to AML1 consensus sequences in DNA. Unlike wild-type AML1, the fusion protein does not initiate p300/CBP-directed histone acetylation and transcriptional activation. Rather, the opposite occurs: through its ETO domain, AML1-ETO recruits N-CoR/Sin3/HDAC1. By permanently tethering this repressive complex to AML1-responsive promoters, AML1-ETO actively suppresses transcription by maintaining the histones in a deacetylated conformation and making DNA inaccessible to the transcriptional apparatus. Inhibition of the expression of AML1-responsive genes leads to a block in myeloid development and leukemic transformation of the maturing hematopoietic progenitors. One might predict that HDAC inhibitors could overcome the effects of AML1-ETO and lead to reversal of the leukemic phenotype; preliminary data suggests that this strategy of chromatin-remodeling therapy holds promise for the treatment of t(8;21) acute myeloid leukemia (see below).

MLL fusions: A SET of alterations.   The MLL locus is involved in a greater assortment of chromosomal rearrangements in leukemias than any other gene (see recent reviews by Downing and Look106 and Cimino et al107). Translocations or inversions of this gene on chromosome 11q23 are associated with a variety of FAB subtypes and some lymphoid malignancies as well (thus the name, Mixed Lineage Leukemia). Because of its involvement in the t(4;11) pediatric B-cell acute lymphoblastic leukemia (ALL),108 MLL is also called ALL1. MLL rearrangement is found in both de novo leukemias and chemotherapy-associated (most often topoisomerase-inhibitor) secondary leukemias. All of the 11q23 leukemias are aggressive, respond poorly to chemotherapy, and have a poor prognosis. More than 40 translocation sites have been identified for MLL, and nearly 20 fusion partners have been cloned. Partial tandem duplication of MLL with an abnormal MLL/MLL fusion occurs in AML patients with the (+11) karyotype109 and is sometimes seen in leukemias with normal karyotype. Possibly relating to a fragile site in the MLL locus, all of the rearrangements cluster within exons 5-11.110

The MLL gene111-114 is more than 100 kb long, encodes an 11.7-kb transcript with 23 exons,110 and gives rise to a protein of 3972 AA. Clues to the function of MLL have come from the identification of domains that share homology with other known proteins. The most significant match is seen in 4 domains that are conserved with the Drosophila protein Trithorax (TRX), giving rise to the alternative name for MLL as the human trithorax gene (HRX or HTRX).111-114 In Drosophila, TRX positively regulates homeotic gene expression,115-118 which in turn directs development of embryonic structures. In mammalian hematopoiesis, MLL is thought to regulate expression of homeobox (HOX) genes,119 which serve a similar critical role as transcriptional activators of developmentally expressed gene families. It follows that dysregulation of HOX gene expression would have global consequences for hematopoietic cells and give rise to aggressive malignant transformation. As expected, murine mll -/- knockouts are embryonic lethal.119 Mll +/- animals have numerous developmental skeletal abnormalities, as well as abnormal hematopoiesis.119

MLL has a series of N-terminal domains known as AT-hooks and a Zn-finger motif in its C-terminus.111-115 As with other AT-hook containing proteins, it is thought that the AT-hooks allow MLL to bind to the minor groove of DNA (Fig 4A). Although it has not been shown to recognize specific DNA sequence motifs, TRX does localize to discrete areas of polytene chromosomes in Drosophila.120 Several of these sites have been identified as regulatory regions of target genes, supporting the hypothesis that TRX and MLL associate physically with cis-acting elements of target genes to facilitate their expression during appropriate stages of development. Unlike TRX, MLL has an N-terminal region that shares homology with the regulatory region, but not the catalytic domain, of DNA methyltransferases112; the significance of this is not yet clear, although one could speculate that this region might participate in chromatin structure recognition. Perhaps key to their function, MLL and TRX share a highly conserved C-terminal 150 AA protein interaction domain, known as the SET domain.120 This region is also found in a number of other proteins that have transcriptional regulatory roles. Through its SET domain, MLL has been shown to bind INI1 and SNR1, 2 proteins that are homologous to members of the SWI/SNF complex.120 SWI/SNF complexes alter chromatin structure in an ATP-dependent fashion (see above). To date, coprecipitation experiments have failed to identify MLL or TRX as part of a stable SWI/SNF-like complex, indicating that the interaction may be a transient one.120

It is reasonable to speculate that MLL serves as a chromatin-binding protein that serves a regulatory function necessary for expression of target genes. Through its SET domain, MLL recruits an SWI/SNF-like ATPase-engine that changes the nucleosomal structure to maintain an open chromatin conformation. Supporting this hypothesis is the observation that initial transcription of downstream targets of MLL occurs normally in mll-null mice; however, in the absence of MLL, transcription of MLL-target genes cannot be maintained.119

It is difficult to propose a single model that would suggest a common mechanism for all of the MLL fusion proteins, including the partial-tandem duplication of MLL itself (Table 3). In all of the MLL fusions (with the exception being the partial-tandem duplication), the N-terminal AT hooks and methyltransferase homology domains are retained, but the C-terminal Zn-finger and SET domains are lost.121 One simple model is that loss of the ability to recruit the SWI/SNF complex disrupts MLL function as a regulator of gene expression. In the tandem MLL duplication, in which the SET domain is preserved, one might postulate that the altered MLL conformation, and the abnormal distance of the SET domain from the N-terminal AT-hooks, might render the MLL protein nonfunctional.

                              
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  		Table 3. MLL Fusion Proteins That May Affect Chromatin Remodeling

However, the picture for 11q23 rearrangements is likely not so simple. Two of its fusion partners,122 AF9 in t(9;11)(p22;q23) and ENL in t(11;19)(q23;p13.3), are homologous to proteins that are themselves associated with the SWI/SNF complex.123 Fusion with the DNA-binding AT-hook domain of MLL might result in permanent tethering of a SWI/SNF-like complex to MLL targets, resulting in constitutive activation of the SWI/SNF chromatin remodeling complex. Another speculative model is that the fusions disrupt MLL-target chromatin structure through recruitment of histone acetylase enzymes. For example, ENL contains a transcriptional activation domain that is retained in the MLL-ENL fusion. Through its activation motif, ENL might tether an HAT-containing coactivator complex to MLL target genes.

Switching HATs.   Two other MLL-fusions potentially act through a similar gain-of-function mechanism involving histone acetylase complexes: t(11;16)(q23;p13) and t(11;23)(q23; q13) fuse the upstream sequences of MLL to CBP124-126 and p300,127 respectively. Most of the domains of CBP and p300 are retained, including those that bind other components of the coactivator complex, as well as the catalytic domain that encodes histone acetylase activity (Fig 4B). For these fusions it is likely that abnormal chromatin remodeling occurs either though constitutive activation of HAT activity or through recruitment of other acetyltransferase components of the coactivator complex.

Histone acetylases are also mutated in the t(8;16)(p11;p13)128 and inv(8)(p11;q13)48 chromosomal rearrangements associated with M4 and M5 AML. In the first, CBP is fused to upstream elements of a gene called MOZ.128 MOZ itself has predicted acetyltransferase activity, although its targets and biological function have not yet been determined. MOZ contains a variant Zn-finger but has not been shown to bind DNA. In the MOZ-CBP fusion the Zn-finger and catalytic domain of MOZ are fused to almost the entire CBP protein. The breakpoint in CBP is similar to that seen in the MLL-CBP fusion (see above). MOZ-CBP therefore has 2 HAT activities.

Similarly, the inv(8) rearrangement fuses the upstream sequences of MOZ to TIF2.48 TIF2 is a homologue of p/CIP, a component of the CBP/p300 coactivator complex. The domain of p/CIP that mediates direct interaction with nuclear hormone receptors is lost in the MOZ-fusion, but the CBP-interaction domain is retained. TIF2 itself is predicted to have acetyltransferase activity, and, like MOZ-CBP, MOZ-TIF2 retains the acetyltransferase homology domains from each of the fusion partners.48 Like the MOZ-CBP rearrangement, such fusion proteins might result in altered chromatin remodeling of MOZ targets either through a dominant-negative effect, altered substrate specificity of the fusion enzyme, or recruitment of a HAT-containing coactivator complex to MOZ targets. Any of these mechanisms might impair normal chromatin remodeling, leading to aberrant transcription. It is worth noting that the MOZ-CBP t(8;16) and MOZ-TIF2 inv(8) leukemias have virtually identical FAB M5 phenotypes,48,128 suggesting that the 2 fusions have a similar final common pathway.


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INTRODUCTION
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Excitement in the field of chromatin structure has been generated with the realization that remodeling mechanisms might be targeted in therapeutic strategies. Preliminary studies, mostly in the in vitro setting, have focused on inhibition of histone deacetylase, in part because HDAC1 was one of the first enzymes identified in nucleosomal remodeling, because its function is best understood, and because it is the only candidate for which specific inhibitors have been identified.

Butyric acid, or butyrate, a physiologic byproduct of colonic bacterial fermentation, was the first identified of the HDAC inhibitors.129-131 It functions as a competitive inhibitor of HDAC, perhaps by mimicking the normal substrate (butyrate is a 4-carbon molecule, whereas acetyl groups are 2-carbon). In micromolar concentrations, butyrate is not specific for HDAC: it also inhibits phosphorylation and methylation of nuclear proteins as well as DNA methylation. Its analog phenylbutyrate132,133 acts in a similar manner.

More specific for HDAC than butyrate or its analogs are trichostatin A134,135 (TSA) and trapoxin136,137 (TPX). TSA, a product of Streptomyces hygropicus, was originally isolated as an antifungal agent. TPX, a cyclic tetrapeptide containing 2 L-phenylalanines, was identified in screens of fungal metabolites that induced morphological reversion of transformed NIH3T3 cells.138 TPX and TSA have emerged as potent inhibitors of the histone deacetylases. TSA reversibly inhibits, whereas TPX irreversibly binds to and inactivates the HDAC enzyme. TSA inhibits histone deacetylation with a Ki of 3.4 nmol/L,135 about 1,000-fold less than butyrate; TPX is even more potent. Unlike butyrate and its analogs, nonspecific inhibition of other enzyme systems has not yet been reported for TSA or TPX. To date, no data are available on the pharmacokinetics or pharmacodynamics of TSA or TPX. Besides TSA, TPX, and butyrate and its derivatives, a number of hybrid polar compounds139,140 have been found to potently inhibit HDAC enzymes, such as suberoylanilide hydroxamic acid and m-carboxycinnamic acid bishydroxamide. Tributyrin,141 a triglyceride with butyrate molecules esterified at the 1, 2, or 3 positions, holds potential as a long-acting, orally administered prodrug.

A major issue concerning the use of such HDAC inhibitors is the potential for modulating chromatin of genes that are not involved in the leukemia or genes in nonleukemic bystander cells. As discussed above, the translocations that cause HDAC to function in inappropriate ways do not truly alter the enzyme itself, but rather bring the normal enzyme into a chromatin environment that it would not otherwise contact. Would HDAC inhibitors have unwanted nonspecific effects that disrupt chromatin of all genes in a cell? Although the explanations are not yet apparent, experience in multiple tissue culture systems has suggested that the effects of HDAC inhibitors are limited. Butyrate, at doses that should inhibit HDAC enzymatic activity, does not kill cells.129 However, the nonspecific effects of butyrate on phosphorylation and methylation make it difficult to draw definite conclusions as to the contribution of HDAC inhibition to its biological effects. TSA has been used in a number of in vitro settings: it was first shown to induce differentiation of MEL cells,142 without having significant apoptotic or transforming effects on the cells. TSA inhibition of HDAC has been shown to increase acetylation of only a subset of promoters,143 suggesting that a minority of genes are regulated through HDAC-dependent chromatin remodeling mechanisms. The observation of normal ordered differentiation in APL model systems with a variety of HDAC inhibitors85-88 supports the notion that these agents do not have global effects on chromatin structure and gene expression.

HDAC inhibitors in leukemia.   We have already alluded to the relationship between RA responsiveness, the HDAC complex, and the RARalpha -fusion proteins in APL. APL has become the paradigm for the application of HDAC inhibitors. As described above, HDAC inhibitors synergize with retinoic acid to overcome the PML-RARalpha and PLZF-RARalpha induced maturation blockade in cell models.85-88 Pandolfi's group87 has shown that, similar to patients with APL, PML-RARalpha transgenic mice responded to RA treatment, whereas PLZF-RARalpha transgenic mice developed RA-resistant leukemia. In vitro, neither RA nor TSA had significant effects on the PLZF-RARalpha blasts, but together they induced differentiation. The interpretation of this data is that RA alone failed to release the N-CoR/Sin3/HDAC1 complex from PLZF-RARalpha ; that TSA acted downstream to inhibit the HDAC complex, but did not induce recruitment of a coactivator complex; and that only in the presence of both molecules could the suppressive effects of PLZF-RARalpha be overcome. These studies are consistent with other reports that suggest that HDAC inhibitors might have a role in APL therapy.85-88 The recent report of blast-cell differentiation and successful remission induction in a patient with PLZF-RARalpha treated with a combination of ATRA and granulocyte colony-stimulating factor (G-CSF)144 raises speculation as to whether G-CSF might alter HDAC activity.

Besides PLZF-RARalpha blasts, some PML-RARalpha -expressing APL cells do not respond to RA alone but may differentiate in response to the combination of RA and an HDAC inhibitor. Several patient samples have been identified to have mutations in the C-terminal region of PML-RARalpha , near the N-CoR binding domain.145 Warrell's group at Memorial Sloan-Kettering has attempted to capitalize on such in vitro observations, reporting the use of the HDAC inhibitor phenylbutyrate in a PML-RARalpha patient who was in her third relapse.146 She had previously been induced with ATRA and chemotherapy, treated in first remission with ATRA and allogeneic bone marrow transplantation, and treated in second relapse with arsenic trioxide after failing reinduction with ATRA or standard chemotherapy. After 11 days on ATRA at 45 mg/m2/d, no change was observed in her bone marrow. At that time, phenylbutyrate was added to her regimen at a dose of 150 mg/kg/d. Immunofluorescence and Western blot analysis of blood and bone marrow mononuclear cells documented a time-dependent increase in histone acetylation (presumably as a result of antagonization of HDAC). Over the next 3 weeks, the doses of both ATRA and phenylbutyrate were increased to 90 mg/m2/d and 210 mg/kg, respectively. A bone marrow performed 2 weeks after the addition of the phenylbutyrate showed a decrease in the percentage of leukemic cells from 23% to 9%. A bone marrow 10 days later showed elimination of leukemic blasts. After a second course of therapy, she achieved a molecular remission (PML-RARalpha negative) and continued to be in remission after 6 months.

Aside from APL, HDAC inhibitors have a potential role in the treatment of AML1-ETO AML (see above). We and others have proposed that AML1-ETO's leukemic potential is mediated by the recruitment of an HDAC-containing complex to AML1-responsive promoters.36-38 In our own experiments,147 we found that TSA or phenylbutyrate was able to partially reverse transcriptional repression mediated by the ETO moiety of AML1-ETO. In vitro treatment of an AML1-ETO cell line (Kasumi-1) with clinically attainable levels of phenylbutyrate induced partial differentiation and apoptosis. Such results may herald the therapeutic application of HDAC inhibitors for t(8;21) AML in the future.

The clinical use of HDAC inhibitors need not be limited to patients with obvious abnormalities in histone deacetylation pathways. In 1983, continuous infusion of butyrate, at a dose of 500 mg/kg/d, was reported to induce a partial remission in a patient with myelomonocytic leukemia.148 No chromosomal abnormalities were noted in this case. It is possible that this patient did have an unrecognized rearrangement that would have aberrantly recruited a histone deacetylase to an abnormal target or that inhibition of HDAC may have compensated for an underactive HAT. Alternatively, the effects might not have been related to fusion gene-specific effects. For example, phenylbutyrate has been reported to upregulate the B7 costimulatory molecule on AML blasts,149 suggesting a role in immune surveillance.

These exciting results with HDAC inhibitors invigorate the search for other means of modulating chromatin remodeling. Despite the current dearth of specific inhibitors of HAT and SWI/SNF enzymes, the development of inhibitory peptides is a potential avenue that has yet to be pursued. Thanks to insights gained from studies of the molecular biology of leukemia, chromatin therapy may emerge as a potent antileukemia strategy of the future.


    ACKNOWLEDGMENT

The authors thank Daniel E. Johnson, Margaret V. Ragni, and Richard A. Steinman for critical reading of the manuscript and Neal Young for encouragement and support.


    FOOTNOTES

Submitted February 4, 1999; accepted April 19, 1999.

Supported by National Institutes of Health Grant No. CA67346 and American Institute for Cancer Research Grant No. 98B039 to R.L.R.

Address reprint requests to Robert L. Redner, MD, E1058 Biomedical Science Tower, University of Pittsburgh Medical Center, 211 Lothrop St, Pittsburgh, PA 15213; e-mail: redner+{at}pitt.edu.


    REFERENCES
TOP
INTRODUCTION
CHROMATIN: BEADS ON A...
NUCLEOSOMAL REMODELING
DISRUPTION OF CHROMATIN...
CHROMATIN THERAPY
REFERENCES

1. Luger K, Mader AW, Richmond RK, Sargent DF, Richmond TJ: Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 389:251, 1997[Medline] [Order article via Infotrieve]

2. Rhodes D: Chromatin structure. The nucleosome core all wrapped up. Nature 389:233, 1997

3. Olins AL, Olins DE: Spheroid chromatin units (nu  bodies). Science 183:330, 1974[Abstract/Free Full Text]

4. Finch JT, Klug A: Solenoidal model for superstructure in chromatin. Proc Natl Acad Sci USA 73:1897, 1976[Abstract/Free Full Text]

5. Cao H, Widlund HR, Simonsson T, Kubista M: TGGA repeats impair nucleosome formation. J Mol Biol 281:253, 1998[Medline] [Order article via Infotrieve]

6. Schild-Poulter C, Sassone-Corsi P, Granger-Schnarr M, Schnarr M: Nucleosome assembly on the human c-fos promoter interferes with transcription factor binding. Nucleic Acids Res 24:4751, 1996[Abstract/Free Full Text]

7. Studitsky VM, Clark DJ, Felsenfeld G: Overcoming a nucleosomal barrier to transcription. Cell 83:19, 1995[Medline] [Order article via Infotrieve]

8. Geraghty DS, Sucic HB, Chen J, Pederson DS: Evidence that partial unwrapping of DNA from nucleosomes facilitates the binding of heat shock factor following DNA replication in yeast. J Biol Chem 273:20463, 1998[Abstract/Free Full Text]

9. Tsukiyama T, Wu C: Chromatin remodeling and transcription. Curr Opin Genet Dev 7:182, 1997[Medline] [Order article via Infotrieve]

10. Bartsch J, Truss M, Bode J, Beato M: Moderate increase in histone acetylation activates the mouse mammary tumor virus promoter and remodels its nucleosome structure. Proc Natl Acad Sci USA 93:10741, 1996[Abstract/Free Full Text]

11. Grunstein M: Histone acetylation in chromatin structure and transcription. Nature 389:349, 1997[Medline] [Order article via Infotrieve]

12. Hebbes TR, Thorne AW, Crane-Robinson C: A direct link between core histone acetylation and transcriptionally active chromatin. EMBO J 7:1395, 1988[Medline] [Order article via Infotrieve]

13. Tse C, Sera T, Wolffe AP, Hansen JC: Disruption of higher-order folding by core histone acetylation dramatically enhances transcription of nucleosomal arrays by RNA polymerase III. Mol Cell Biol 18:4629, 1998[Abstract/Free Full Text]

14. Vettese-Dadey M, Grant PA, Hebbes TR, Crane-Robinson C, Allis CD, Workman JL: Acetylation of histone H4 plays a primary role in enhancing transcription factor binding to nucleosomal DNA in vitro. EMBO J 15:2508, 1996[Medline] [Order article via Infotrieve]

15. Walia H, Chen HY, Sun JM, Holth LT, Davie JR: Histone acetylation is required to maintain the unfolded nucleosome structure associated with transcribing DNA. J Biol Chem 273:14516, 1998[Abstract/Free Full Text]

16. Ura K, Kurumizaka H, Dimitrov S, Almouzni G, Wolffe AP: Histone acetylation: Influence on transcription, nucleosome mobility and positioning, and linker histone-dependent transcriptional repression. EMBO J 16:2096, 1997[Medline] [Order article via Infotrieve]

17. Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A: Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393:386, 1998[Medline] [Order article via Infotrieve]

18. Tremethick DJ, Hyman L: High mobility group protein 14 and 17 can prevent the close packing of nucleosomes by increasing the strength of protein contacts in the linker DNA. J Biol Chem 271:12009, 1996[Abstract/Free Full Text]

19. Postnikov YV, Herrera JE, Hock R, Scheer U, Bustin M: Clusters of nucleosomes containing chromosomal protein HMG-17 in chromatin. J Mol Biol 274:454, 1997[Medline] [Order article via Infotrieve]

20. Glass CK, Rose DW, Rosenfeld MG: Nuclear receptor coactivators. Curr Opin Cell Biol 9:222, 1997[Medline] [Order article via Infotrieve]

21. Utley RT, Ikeda K, Grant PA, Cote J, Steger DJ, Eberharter A, John S, Workman JL: Transcriptional activators direct histone acetyltransferase complexes to nucleosomes. Nature 394:498, 1998[Medline] [Order article via Infotrieve]

22. Evans R: The steroid and thyroid hormone receptor superfamily. Nature 240:889, 1988

23. Yu VC, Delsert C, Andersen B, Holloway JM, Devary OV, Naar AM, Kim SY, Boutin JM, Glass CK, Rosenfeld MG: RXR beta: A coregulator that enhances binding of retinoic acid, thyroid hormone, and vitamin D receptors to their cognate response elements. Cell 67:1251, 1991[Medline] [Order article via Infotrieve]

24. 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]

25. 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]

25a. Yang N, Schule R, Mangelsdorf DJ, Evans RM: Characterization of DNA binding and retinoic acid binding properties of retinoic acid receptor. Proc Natl Acad Sci USA 9:3559, 1991

26. Horlein AJ, Naar AM, Heinzel T, Torchia J, Gloss B, Kurokawa R, Ryan A, Kamei Y, Soderstrom M, Glass CK, Rosenfeld MG: Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377:397, 1995[Medline] [Order article via Infotrieve]

27. Kurokawa R, Soderstrom M, Horlein A, Halachmi S, Brown M, Rosenfeld MG, Glass CK: Polarity-specific activities of retinoic acid receptors determined by a co-repressor. Nature 377:451, 1995[Medline] [Order article via Infotrieve]

28. Chen JD, Evans RM: A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377:454, 1995[Medline] [Order article via Infotrieve]

29. Chen JD, Umesono K, Evans RM: SMRT isoforms mediate repression and anti-repression of nuclear receptor heterodimers. Proc Natl Acad Sci USA 93:7567, 1996[Abstract/Free Full Text]

30. Alland L, Muhle R, Hou H Jr, Potes J, Chin L, Schreiber-Agus N, DePinho RA: Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression. Nature 387:49, 1997[Medline] [Order article via Infotrieve]

31. Laherty CD, Yang WM, Sun JM, Davie JR, Seto E, Eisenman RN: Histone deacetylases associated with the mSin3 corepressor mediate Mad transcriptional repression. Cell 89:349, 1997[Medline] [Order article via Infotrieve]

32. Heinzel T, Lavinsky RM, Mullen TM, Soderstrom M, Laherty CD, Torchia J, Yang WM, Brard G, Ngo SD, Davie JR, Seto E, Eisenman RN, Rose DW, Glass CK, Rosenfeld MG: A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature 387:43, 1997[Medline] [Order article via Infotrieve]

33. Hassig CA, Tong JK, Fleischer TC, Owa T, Grable PG, Ayer DE, Schreiber SL: A role for histone deacetylase activity in HDAC1-mediated transcriptional repression. Proc Natl Acad Sci USA 95:3519, 1998[Abstract/Free Full Text]

34. Ayer DE, Lawrence QA, Eisenman RN: Mad-Max transcriptional repression is mediated by ternary complex formation with mammalian homologs of yeast repressor Sin3. Cell 80:767, 1995[Medline] [Order article via Infotrieve]

35. Harper SE, Qiu Y, Sharp PA: Sin3 corepressor function in Myc-induced transcription and transformation. Proc Natl Acad Sci USA 93:8536, 1996[Abstract/Free Full Text]

36. Wang JX, Hoshino T, Redner RL, Kajigaya S, Liu JM: ETO, fusion partner in t(8-21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex. Proc Natl Acad Sci USA 95:10860, 1998[Abstract/Free Full Text]

37. Gelmetti V, Zhang JS, Fanelli M, Minucci S, Pelicci PG, Lazar MA: Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. Mol Cell Biol 18:7185, 1998[Abstract/Free Full Text]

38. Lutterbach B, Westendorf JJ, Linggi B, Patten A, Moniwa M, Davie JR, Huynh KD, Bardwell VJ, Lavinsky RM, Rosenfeld MG, Glass C, Seto E, Hiebert SW: ETO, a target of t(8-21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors. Mol Cell Biol 18:7176, 1998[Abstract/Free Full Text]

39. Driscoll JE, Seachord CL, Lupisella JA, Darveau RP, Reczek PR: Ligand-induced conformational changes in the human retinoic acid receptor detected using monoclonal antibodies. J Biol Chem 271:22969, 1996[Abstract/Free Full Text]

40. Heery DM, Kalkhoven E, Hoare S, Parker MG: A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 387:733, 1997[Medline] [Order article via Infotrieve]

41. Lin BC, Hong SH, Krig S, Yoh SM, Privalsky ML: A conformational switch in nuclear hormone receptors is involved in coupling hormone binding to corepressor release. Mol Cell Biol 17:6131, 1997[Abstract]

42. Jenster G, Spencer TE, Burcin MM, Tsai SY, Tsai MJ, O'Malley BW: Steroid receptor induction of gene transcription: A two-step model. Proc Natl Acad Sci USA 94:7879, 1997[Abstract/Free Full Text]

43. Torchia J, Rose DW, Inostroza J, Kamei Y, Westin S, Glass CK, Rosenfeld MG: The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 387:677, 1997[Medline] [Order article via Infotrieve]

44. Blanco JC, Minucci S, Lu J, Yang XJ, Walker KK, Chen H, Evans RM, Nakatani Y, Ozato K: The histone acetylase PCAF is a nuclear receptor coactivator. Genes Dev 12:1638, 1998[Abstract/Free Full Text]

45. Beato M, Candau R, Chavez S, Mows C, Truss M: Interaction of steroid hormone receptors with transcription factors involves chromatin remodelling. J Steroid Biochem Mol Biol 56:47, 1996[Medline] [Order article via Infotrieve]

46. McKenna NJ, Nawaz Z, Tsai SY, Tsai MJ, O'Malley BW: Distinct steady-state nuclear receptor coregulator complexes exist in vivo. Proc Natl Acad Sci USA 95:11697, 1998[Abstract/Free Full Text]

47. Li H, Gomes PJ, Chen JD: RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2. Proc Natl Acad Sci USA 94:8479, 1997[Abstract/Free Full Text]

48. Carapeti M, Aguiar RC, Goldman JM, Cross NC: A novel fusion between MOZ and the nuclear receptor coactivator TIF2 in acute myeloid leukemia. Blood 91:3127, 1998[Abstract/Free Full Text]

49. Eckner R: p300 and CBP as transcriptional regulators and targets of oncogenic events. Biol Chem 377:685, 1996

50. Martinez-Balbas MA, Bannister AJ, Martin K, Haus-Seuffert P, Meisterernst M, Kouzarides T: The acetyltransferase activity of CBP stimulates transcription. EMBO J 17:2886, 1998[Medline] [Order article via Infotrieve]

51. Giles RH, Peters D, Breuning MH: Conjunction dysfunction---CBP/p300 in human disease. Trends Genet 14:178, 1998[Medline] [Order article via Infotrieve]

52. Imhof A, Yang XJ, Ogryzko VV, Nakatani Y, Wolffe AP, Ge H: Acetylation of general transcription factors by histone acetyltransferases. Curr Biol 7:689, 1997[Medline] [Order article via Infotrieve]

53. Spencer TE, Jenster G, Burcin MM, Allis CD, Zhou J, Mizzen CA, McKenna NJ, Onate SA, Tsai SY, Tsai MJ, O'Malley BW: Steroid receptor coactivator-1 is a histone acetyltransferase. Nature 389:194, 1997[Medline] [Order article via Infotrieve]

54. Razin A, Cedar H: DNA methylation and gene expression. Microbiol Rev 55:451, 1991[Abstract/Free Full Text]

55. Davey C, Pennings S, Allan J: CpG methylation remodels chromatin structure in vitro. J Mol Biol 267:276, 1997[Medline] [Order article via Infotrieve]

56. Nan X, Campoy FJ, Bird A: MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell 88:471, 1997[Medline] [Order article via Infotrieve]

57. Jones PA: Altering gene expression with 5-azacytidine. Cell 40:485, 1985[Medline] [Order article via Infotrieve]

58. Burns LG, Peterson CL: The yeast SWI-SNF complex facilitates binding of a transcriptional activator to nucleosomal sites in vivo. Mol Cell Biol 17:4811, 1997[Abstract]

59. Cote J, Peterson CL, Workman JL: Perturbation of nucleosome core structure by the SWI/SNF complex persists after its detachment, enhancing subsequent transcription factor binding. Proc Natl Acad Sci USA 95:4947, 1998[Abstract/Free Full Text]

60. Logie C, Peterson CL: Catalytic activity of the yeast SWI/SNF complex on reconstituted nucleosome arrays. EMBO J 16:6772, 1997[Medline] [Order article via Infotrieve]

61. Schnitzler G, Sif S, Kingston RE: Human SWI/SNF interconverts a nucleosome between its base state and a stable remodeled state. Cell 94:17, 1998[Medline] [Order article via Infotrieve]

62. Ryan MP, Jones R, Morse RH: SWI-SNF complex participation in transcriptional activation at a step subsequent to activator binding. Mol Cell Biol 18:1774, 1998[Abstract/Free Full Text]

63. Mizuguchi G, Tsukiyama T, Wisniewski J, Wu C: Role of nucleosome remodeling factor NURF in transcriptional activation of chromatin. Mol Cell 1:141, 1997[Medline] [Order article via Infotrieve]

64. Cairns BR, Lorch Y, Li Y, Zhang M, Lacomis L, Erdjument-Bromage H, Tempst P, Du J, Laurent B, Kornberg RD: RSC, an essential, abundant chromatin-remodeling complex. Cell 87:1249, 1996[Medline] [Order article via Infotrieve]

65. Lorch Y, Cairns BR, Zhang M, Kornberg RD: Activated RSC-nucleosome complex and persistently altered form of the nucleosome. Cell 94:29, 1998[Medline] [Order article via Infotrieve]

66. Ito T, Bulger M, Pazin MJ, Kobayashi R, Kadonaga JT: ACF, an ISWI-containing and ATP-utilizing chromatin assembly and remodeling factor. Cell 90:145, 1997[Medline] [Order article via Infotrieve]

67. Auble DT, Wang DY, Post KW, Hahn S: Molecular analysis of the SNF2/SWI2 protein family member Mot1, an ATP-driven enzyme that dissociates TATA-binding protein from DNA. Mol Cell Biol 17:4842, 1997[Abstract]

68. Wang W, Cote J, Xue Y, Zhou S, Khavari PA, Biggar SR, Muchardt C, Kalpana GV, Goff SP, Yaniv M, Workman JL, Crabtree GR: Purification and biochemical heterogeneity of the mammalian SWI-SNF complex. EMBO J 15:5370, 1996[Medline] [Order article via Infotrieve]

69. Dallas PB, Cheney IW, Liao DW, Bowrin V, Byam W, Pacchione S, Kobayashi R, Yaciuk P, Moran E: p300/CREB binding protein-related protein p270 is a component of mammalian SWI/SNF complexes. Mol Cell Biol 18:3596, 1998[Abstract/Free Full Text]

70. Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhoa L, Gu LJ, Wang ZY: Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72:567, 1988[Abstract/Free Full Text]

71. Warrell RJ, Frankel SR, Miller WJ, Scheinberg DA, Itri LM, Hittelman WN, Vyas R, Andreeff M, Tafuri A, Jakubowski A, Gabrilove J, Gordon MS, Dmitrovsky E: Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med 324:1385, 1991[Abstract]

72. Warrell R Jr, de The H, Wang ZY, Degos L: Acute promyelocytic leukemia. N Engl J Med 329:177, 1993[Free Full Text]

73. Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A, Shepherd L, Willman C, Bloomfield CD, Rowe JM, Wiernik PH: All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 337:1021, 1997[Abstract/Free Full Text]

74. 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]

75. Tsai S, Bartelmez S, Heyman R, Damm K, Evans R, Collins S: A mutated retinoic acid receptor-alpha exhibiting dominant-negative activity alters the lineage evelopment of a multipotent hematopoietic cell line. Genes Dev 6:2258, 1992[Abstract/Free Full Text]

76. Borrow J, Goddard AD, Sheer D, Solomon E: Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17. Science 249:1577, 1990[Abstract/Free Full Text]

77. Kakizuka A, Miller WJ, Umesono K, Warrell RJ, 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]

78. 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]

79. 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]

80. 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]

81. Wells RA, Hummel JL, De Koven A, Zipursky A, Kirby M, Dube I, Kamel-Reid S: A new variant translocation in acute promyelocytic leukaemia: Molecular characterization and clinical correlation. Leukemia 10:735, 1996[Medline] [Order article via Infotrieve]

82. Licht JD, Chomienne C, Goy A, Chen A, Scott AA, Head DR, Michaux JL, Wu Y, DeBlasio A, Miller WH, Zelenetz AD, Wilman 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]

83. Licht JD, Shaknovitch R, English MA, Melnick A, Li J-Y, Reddy JC, Dong S, Chen S-J, 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]

84. 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]

85. Grignani F, Dematteis S, Nervi C, Tomassoni L, Gelmetti V, Cioce M, Fanelli M, Ruthardt M, Ferrara FF, Zamir I, Seiser C, Grignani F, Lazar MA, Minucci S, Pelicci PG: Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. Nature 391:815, 1998[Medline] [Order article via Infotrieve]

86. Guidez F, Ivins S, Zhu J, Soderstrom M, Waxman S, Zelent A: Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RAR-alpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia. Blood 91:2634, 1998[Abstract/Free Full Text]

87. He LZ, Guidez F, Tribioli C, Peruzzi D, Ruthardt M, Zelent A, Pandolfi PP: Distinct interactions of PML-RAR-alpha and PLZF-RAR-alpha with co-repressors determine differential responses to RA in APL. Nat Genet 18:126, 1998[Medline] [Order article via Infotrieve]

88. Lin RJ, Nagy L, Inoue S, Shao WL, Miller WH, Evans RM: Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature 391:811, 1998[Medline] [Order article via Infotrieve]

89. Redner RL, Corey SJ, Rush EA: Differentiation of t(5;17) variant acute promyelocytic leukemic blasts by all-trans retinoic acid. Leukemia 11:1014, 1997[Medline] [Order article via Infotrieve]

90. Ahmad KF, Engel CK, Prive GG: Crystal structure of the BTB domain from PLZF. Proc Natl Acad Sci USA 95:12123, 1998[Abstract/Free Full Text]

91. Li X, Lopez-Guisa JM, Ninan N, Weiner EJ, Rauscher F3, Marmorstein R: Overexpression, purification, characterization, and crystallization of the BTB/POZ domain from the PLZF oncoprotein. J Biol Chem 272:27324, 1997[Abstract/Free Full Text]

92. Hong SH, David G, Wong CW, Dejean A, Privalsky ML: SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor alpha (RARalpha) and PLZF-RARalpha oncoproteins associated with acute promyelocytic leukemia. Proc Natl Acad Sci USA 94:9028, 1997[Abstract/Free Full Text]

93. David G, Alland L, Hong SH, Wong CW, DePinho RA, Dejean A: Histone deacetylase associated with mSin3A mediates repression by the acute promyelocytic leukemia-associated PLZF protein. Oncogene 16:2549, 1998[Medline] [Order article via Infotrieve]

94. Dhordain P, Albagli O, Lin RJ, Ansieau S, Quief S, Leutz A, Kerckaert JP, Evans RM, Leprince D: Corepressor SMRT binds the BTB/POZ repressing domain of the LAZ3/BCL6 oncoprotein. Proc Natl Acad Sci USA 94:10762, 1997[Abstract/Free Full Text]

95. Guidez F, Huang W, Tong JH, Dubois C, Balitrand N, Waxman S, Michaux JL, Martiat P, Degos L, Chen Z, 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]

96. Hiebert SW, Downing JR, Lenny N, Meyers S: Transcriptional regulation by the t(8;21) fusion protein, AML-1/ETO. Curr Top Microbiol Immunol 211:253, 1996[Medline] [Order article via Infotrieve]

97. Bloomfield CD, Shuma C, Regal L, Philip PP, Hossfeld DK, Hagemeijer AM, Garson OM, Peterson BA, Sakurai M, Alimena G, Berger R, Rowley JD, Ruutu T, Mitelman F, Dewald GW, Swansbury J: Long-term survival of patients with acute myeloid leukemia: A third follow-up of the Fourth International Workshop on Chromosomes in Leukemia. Cancer 80:2191, 1997[Medline] [Order article via Infotrieve]

98. Bennett JM, Young ML, Andersen JW, Cassileth PA, Tallman MS, Paietta E, Wiernik PH, Rowe JM: Long-term survival in acute myeloid leukemia: The Eastern Cooperative Oncology Group experience. Cancer 80:2205, 1997[Medline] [Order article via Infotrieve]

99. 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]

100. Kitabayashi I, Yokoyama A, Shimizu K, Ohki M: Interaction and functional cooperation of the leukemia-associated factors AML1 and p300 in myeloid cell differentiation. EMBO J 17:2994, 1998[Medline] [Order article via Infotrieve]

101. 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]

102. Yergeau DA, Hetherington CJ, Wang Q, Zhang P, Sharpe AH, Binder M, Marin-Padilla M, Tenen DG, Speck NA, Zhang DE: Embryonic lethality and impairment of haematopoiesis in mice heterozygous for an AML1-ETO fusion gene. Nat Genet 15:303, 1997[Medline] [Order article via Infotrieve]

103. Lenny N, Meyers S, Hiebert SW: Functional domains of the t(8;21) fusion protein, AML-1/ETO. Oncogene 11:1761, 1995[Medline] [Order article via Infotrieve]

104. Erickson PF, Dessev G, Lasher RS, Philips G, Robinson M, Drabkin HA: ETO and AML1 phosphoproteins are expressed in CD34+ hematopoietic progenitors: Implications for t(8;21) leukemogenesis and monitoring residual disease. Blood 88:1813, 1996[Abstract/Free Full Text]

105. Wang J, Wang M, Liu JM: Transformation properties of the ETO gene, fusion partner in t(8;21) leukemias. Cancer Res 57:2951, 1997[Abstract/Free Full Text]

106. Downing JR, Look AT: MLL fusion genes in the 11q23 acute leukemias. Cancer Treat Res 84:73, 1996[Medline] [Order article via Infotrieve]

107. Cimino G, Rapanotti MC, Sprovieri T, Elia L: ALL1 gene alterations in acute leukemia: Biological and clinical aspects. Haematologica 83:350, 1998[Abstract/Free Full Text]

108. Janssen JW, Ludwig WD, Borkhardt A, Spadinger U, Rieder H, Fonatsch C, Hossfeld DK, Harbott J, Schulz AS, Repp R, Sykkora KW, Hoelzer D, Bartram CR: Pre-pre-B acute lymphoblastic leukemia: High frequency of alternatively spliced ALL1-AF4 transcripts and absence of minimal residual disease during complete remission. Blood 84:3835, 1994[Abstract/Free Full Text]

109. Caligiuri MA, Strout MP, Schichman SA, Mrozek K, Arthur DC, Herzig GP, Baer MR, Schiffer CA, Heinonen K, Knuutila S, Nousiainen T, Ruutu T, Block AW, Schulman P, Pedersen-Bjergaard J, Croce CM, Bloomfield CD: Partial tandem duplication of ALL1 as a recurrent molecular defect in acute myeloid leukemia with trisomy 11. Cancer Res 56:1418, 1996[Abstract/Free Full Text]

110. Rasio D, Schichman SA, Negrini M, Canaani E, Croce CM: Complete exon structure of the ALL1 gene. Cancer Res 56:1766, 1996[Abstract/Free Full Text]

111. Djabali M, Selleri L, Parry P, Bower M, Young BD, Evans GA: A trithorax-like gene is interrupted by chromosome 11q23 translocations in acute leukaemias. Nat Genet 2:113, 1992[Medline] [Order article via Infotrieve]

112. Ma Q, Alder H, Nelson KK, Chatterjee D, Gu Y, Nakamura T, Canaani E, Croce CM, Siracusa LD, Buchberg AM: Analysis of the murine All-1 gene reveals conserved domains with human ALL-1 and identifies a motif shared with DNA methyltransferases. Proc Natl Acad Sci USA 90:6350, 1993[Abstract/Free Full Text]

113. Parry P, Djabali M, Bower M, Khristich J, Waterman M, Gibbons B, Young BD, Evans G: Structure and expression of the human trithorax-like gene 1 involved in acute leukemias. Proc Natl Acad Sci USA 90:4738, 1993[Abstract/Free Full Text]

114. 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]

115. Breen TR, Harte PJ: Molecular characterization of the trithorax gene, a positive regulator of homeotic gene expression in Drosophila. Mech Dev 35:113, 1991[Medline] [Order article via Infotrieve]

116. Breen TR, Harte PJ: Trithorax regulates multiple homeotic genes in the bithorax and Antennapedia complexes and exerts different tissue-specific, parasegment-specific and promoter-specific effects on each. Development 117:119, 1993[Abstract/Free Full Text]

117. Mazo AM, Huang DH, Mozer BA, Dawid IB: The trithorax gene, a trans-acting regulator of the bithorax complex in Drosophila, encodes a protein with zinc-binding domains. Proc Natl Acad Sci USA 87:2112, 1990[Abstract/Free Full Text]

118. Orlando V, Jane EP, Chinwalla V, Harte PJ, Paro R: Binding of trithorax and polycomb proteins to the bithorax complex---Dynamic changes during early drosophila embryogenesis. EMBO J 17:5141, 1998[Medline] [Order article via Infotrieve]

119. Yu BD, Hanson RD, Hess JL, Horning SE, Korsmeyer SJ: MLL, a mammalian trithorax-group gene, functions as a transcriptional maintenance factor in morphogenesis. Proc Natl Acad Sci USA 95:10632, 1998[Abstract/Free Full Text]

120. Rozenblatt-Rosen O, Rozovskaia T, Burakov D, Sedkov Y, Tillib S, Blechman J, Nakamura T, Croce CM, Mazo A, Canaani E: The C-terminal SET domains of ALL-1 and Trithorax interact with the INI1 and SNR1 proteins, components of the SWI/SNF complex. Proc Natl Acad Sci USA 95:4152, 1998[Abstract/Free Full Text]

121. 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]

122. Nakamura T, Alder H, Gu Y, Prasad R, Canaani O, Kamada N, Gale RP, Lange B, Crist WM, Nowell PC, Croce CM, Canaani E: Genes on chromosomes 4, 9, and 19 involved in 11q23 abnormalities in acute leukemia share sequence homology and/or common motifs. Proc Natl Acad Sci USA 90:4631, 1993[Abstract/Free Full Text]

123. Cairns BR, Henry NL, Kornberg RD: TFG/TAF30/ANC1, a component of the yeast SWI/SNF complex that is similar to the leukemogenic proteins ENL and AF-9. Mol Cell Biol 16:3308, 1996[Abstract]

124. Sobulo OM, Borrow J, Tomek R, Reshmi S, Harden A, Schlegelberger B, Housman D, Doggett NA, Rowley JD, Zeleznik-Le NJ: MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16)(q23;p13.3). Proc Natl Acad Sci USA 94:8732, 1997[Abstract/Free Full Text]

125. Rowley JD, Reshmi S, Sobulo O, Musvee T, Anastasi J, Raimondi S, Schneider NR, Barredo JC, Cantu ES, Schlegelberger B, Behm F, Doggett NA, Borrow J, Zeleznik-Le N: All patients with the T(11;16)(q23;p13.3) that involves MLL and CBP have treatment-related hematologic disorders. Blood 90:535, 1997[Abstract/Free Full Text]

126. Taki T, Sako M, Tsuchida M, Hayashi Y: The t(11;16)(q23;p13) translocation in myelodysplastic syndrome fuses the MLL gene to the CBP gene. Blood 89:3945, 1997[Abstract/Free Full Text]

127. Ida K, Kitabayashi I, Taki T, Taniwaki M, Noro K, Yamamoto M, Ohki M, Hayashi Y: Adenoviral E1A-associated protein p300 is involved in acute myeloid leukemia with t(11;22)(q23;q13). Blood 90:4699, 1997[Abstract/Free Full Text]

128. Borrow J, Stanton V Jr, Andresen JM, Becher R, Behm FG, Chaganti RS, Civin CI, Disteche C, Dube I, Frischauf AM, Horsman D, Mitelman F, Volinia S, Watmore AE, Housman DE: The translocation t(8;16)(p11;p13) of acute myeloid leukaemia fuses a putative acetyltransferase to the CREB-binding protein. Nat Genet 14:33, 1996[Medline] [Order article via Infotrieve]

129. Candido EP, Reeves R, Davie JR: Sodium butyrate inhibits histone deacetylation in cultured cells. Cell 14:105, 1978[Medline] [Order article via Infotrieve]

130. Boffa LC, Vidali G, Mann RS, Allfrey VG: Suppression of histone deacetylation in vivo and in vitro by sodium butyrate. J Biol Chem 253:3364, 1978[Abstract/Free Full Text]

131. Vidali G, Boffa LC, Bradbury EM, Allfrey VG: Butyrate suppression of histone deacetylation leads to accumulation of multiacetylated forms of histones H3 and H4 and increased DNase I sensitivity of the associated DNA sequences. Proc Natl Acad Sci USA 75:2239, 1978[Abstract/Free Full Text]

132. Elder DJ, Morgan P, Kelly DJ: Anaerobic degradation of trans-cinnamate and omega-phenylalkane carboxylic acids by the photosynthetic bacterium Rhodopseudomonas palustris: Evidence for a beta-oxidation mechanism. Arch Microbiol 157:148, 1992[Medline] [Order article via Infotrieve]

133. Samid D, Hudgins WR, Shack S, Liu L, Prasanna P, Myers CE: Phenylacetate and phenylbutyrate as novel, nontoxic differentiation inducers. Adv Exp Med Biol 501, 1997

134. Yoshida M, Beppu T: Reversible arrest of proliferation of rat 3Y1 fibroblasts in both the G1 and G2 phases by trichostatin A. Exp Cell Res 177:122, 1988[Medline] [Order article via Infotrieve]

135. Yoshida M, Kijima M, Akita M, Beppu T: Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A. J Biol Chem 265:17174, 1990[Abstract/Free Full Text]

136. Itazaki H, Nagashima K, Sugita K, Yoshida H, Kawamura Y, Yasuda Y, Matsumoto K, Ishii K, Uotani N, Nakai H, Terui A, Yoshimatsu S, Ikanishi Y, Nakagawa Y: Isolation and structural elucidation of new cyclotetrapeptides, trapoxins A and B, having detransformation activities as antitumor agents. J Antibiot 43:1524, 1990[Medline] [Order article via Infotrieve]

137. Kijima M, Yoshida M, Sugita K, Horinouchi S, Beppu T: Trapoxin, an antitumor cyclic tetrapeptide, is an irreversible inhibitor of mammalian histone deacetylase. J Biol Chem 268:22429, 1993[Abstract/Free Full Text]

138. Yoshida M, Horinouchi S, Beppu T: Trichostatin A and trapoxin: Novel chemical probes for the role of histone acetylation in chromatin structure and function. Bioessays 17:423, 1995[Medline] [Order article via Infotrieve]

139. Richon VM, Webb Y, Merger R, Sheppard T, Jursic B, Ngo L, Civoli F, Breslow R, Rifkind RA, Marks PA: Second generation hybrid polar compounds are potent inducers of transformed cell differentiation. Proc Natl Acad Sci USA 93:5705, 1996[Abstract/Free Full Text]

140. Richon VM, Emiliani S, Verdin E, Webb Y, Breslow R, Rifkind RA, Marks PA: A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases. Proc Natl Acad Sci USA 95:3003, 1998[Abstract/Free Full Text]

141. Newmark HL, Young CW: Butyrate and phenylacetate as differentiating agents: practical problems and opportunities. J Cell Biochem 22:247, 1995 (suppl 1)

142. Yoshida M, Nomura S, Beppu T: Effects of trichostatins on differentiation of murine erythroleukemia cells. Cancer Res 47:3688, 1987[Abstract/Free Full Text]

143. Van Lint C, Emiliani S, Verdin E: The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation. Gene Exp 5:245, 1996

144. Jansen JH, de Ridder MC, Geertsma WMC, Erpelinck CAJ, Smit B, Slater R, vd Reijden BA, Greef GE, Sonneveld P, Lowenberg B: Complete remission of t(11;17) positive acute promyelocytic leukemia by all-trans retinoic acid and G-CSF. Blood 92:402a, 1998 (abstr, suppl 1)

145. Ding W, Li YP, Nobile LM, Grills G, Carrera I, Paietta E, Tallman M, Wiernik PH, Gallagher RE: Leukemic cellular retinoic acid resistance and missense mutations in the PML-RARalpha fusion gene after relapse of acute promyelocytic leukemia from treatment with all-trans retinoic acid and intensive chemotherapy. Blood 92:1172, 1998[Abstract/Free Full Text]

146. Warrell RP, He LZ, Richon V, Calleja E, Pandolfi PP: Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Nat Cancer Inst 90:1621, 1998[Abstract/Free Full Text]

147. Wang JX, Saunthararajah Y, Redner RL, Liv JM: Inhibitors of histone deacetylase relieve ETO-mediated repression and induce differentiation of AML1-ETO leukemia cells. Cancer Res (in press)

148. Novogrodsky A, Dvir A, Ravid A, Shkolnik T, Stenzel KH, Rubin AL, Zaizov R: Effect of polar organic compounds on leukemic cells. Butyrate-induced partial remission of acute myelogenous leukemia in a child. Cancer 51:9, 1983[Medline] [Order article via Infotrieve]

149. Mizuno S, Tokunaga Y, Maeda M, Inaba S, Miyamoto T, Akashi K, Godno H, Niho Y: Inhibitor of histone deacetylase upregulates B7 molecules in acute myelogenous leukemia. Blood 92:616a, 1998 (abstr, suppl 1)

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[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
S. D. Gore, L.-J. Weng, S. Zhai, W. D. Figg, R. C. Donehower, G. J. Dover, M. Grever, C. A. Griffin, L. B. Grochow, E. K. Rowinsky, et al.
Impact of the Putative Differentiating Agent Sodium Phenylbutyrate on Myelodysplastic Syndromes and Acute Myeloid Leukemia
Clin. Cancer Res., August 1, 2001; 7(8): 2330 - 2339.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
H. Mabuchi, H. Fujii, G. Calin, H. Alder, M. Negrini, L. Rassenti, T. J. Kipps, F. Bullrich, and C. M. Croce
Cloning and Characterization of CLLD6, CLLD7, and CLLD8, Novel Candidate Genes for Leukemogenesis at Chromosome 13q14, a Region Commonly Deleted in B-Cell Chronic Lymphocytic Leukemia
Cancer Res., April 1, 2001; 61(7): 2870 - 2877.
[Abstract] [Full Text]

Home page
 Cancer Res.Home page
C. Nervi, U. Borello, F. Fazi, V. Buffa, P. G. Pelicci, and G. Cossu
Inhibition of Histone Deacetylase Activity by Trichostatin A Modulates Gene Expression during Mouse Embryogenesis without Apparent Toxicity
Cancer Res., February 1, 2001; 61(4): 1247 - 1249.
[Abstract] [Full Text]

Home page
 Cancer Res.Home page
F. F. Ferrara, F. Fazi, A. Bianchini, F. Padula, V. Gelmetti, S. Minucci, M. Mancini, P. G. Pelicci, F. L. Coco, and C. Nervi
Histone Deacetylase-targeted Treatment Restores Retinoic Acid Signaling and Differentiation in Acute Myeloid Leukemia
Cancer Res., January 1, 2001; 61(1): 2 - 7.
[Abstract] [Full Text]

Home page
 J. Med. Genet.Home page
C. A Johnson
Chromatin modification and disease
J. Med. Genet., December 1, 2000; 37(12): 905 - 915.
[Full Text]

Home page
 BloodHome page
T. Maeda, M. Towatari, H. Kosugi, and H. Saito
Up-regulation of costimulatory/adhesion molecules by histone deacetylase inhibitors in acute myeloid leukemia cells
Blood, December 1, 2000; 96(12): 3847 - 3856.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
J. L. Hecht and J. C. Aster
Molecular Biology of Burkitt's Lymphoma
J. Clin. Oncol., November 1, 2000; 18(21): 3707 - 3721.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
A. Melnick, K. F. Ahmad, S. Arai, A. Polinger, H. Ball, K. L. Borden, G. W. Carlile, G. G. Prive, and J. D. Licht
In-Depth Mutational Analysis of the Promyelocytic Leukemia Zinc Finger BTB/POZ Domain Reveals Motifs and Residues Required for Biological and Transcriptional Functions
Mol. Cell. Biol., September 1, 2000; 20(17): 6550 - 6567.
[Abstract] [Full Text]

Home page
 Cancer Res.Home page
D. W. Lee, K. Zhang, Z.-Q. Ning, E. H. Raabe, S. Tintner, R. Wieland, B. J. Wilkins, J. M. Kim, R. I. Blough, and R. J. Arceci
Proliferation-associated SNF2-like Gene (PASG): A SNF2 Family Member Altered in Leukemia1
Cancer Res., July 1, 2000; 60(13): 3612 - 3622.
[Abstract] [Full Text]

Home page
 BloodHome page
R. L. Redner, J. D. Chen, E. A. Rush, H. Li, and S. L. Pollock
The t(5;17) acute promyelocytic leukemia fusion protein NPM-RAR interacts with co-repressor and co-activator proteins and exhibits both positive and negative transcriptional properties
Blood, April 15, 2000; 95(8): 2683 - 2690.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
A. L. Kung, V. I. Rebel, R. T. Bronson, L.-E. Ch'ng, C. A. Sieff, D. M. Livingston, and T.-P. Yao
Gene dose-dependent control of hematopoiesis and hematologic tumor suppression by CBP
Genes & Dev., February 1, 2000; 14(3): 272 - 277.
[Abstract] [Full Text]

Home page
 ASH Education BookHome page
N. C. Gorin, E. Estey, R. J. Jones, H. I. Levitsky, I. Borrello, and S. Slavin
New Developments in the Therapy of Acute Myelocytic Leukemia
Hematology, January 1, 2000; 2000(1): 69 - 89.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
K. Kaushansky
Blood: New designs for a new millennium
Blood, January 1, 2000; 95(1): 1 - 6.
[Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
E. Hu, Z. Chen, T. Fredrickson, Y. Zhu, R. Kirkpatrick, G.-F. Zhang, K. Johanson, C.-M. Sung, R. Liu, and J. Winkler
Cloning and Characterization of a Novel Human Class I Histone Deacetylase That Functions as a Transcription Repressor
J. Biol. Chem., May 12, 2000; 275(20): 15254 - 15264.
[Abstract] [Full Text] [PDF]

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