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NEOPLASIA
From the Shanghai Institute of Hematology,
Ruijin Hospital, Shanghai Second Medical University, the Institute of
Cell Biology, Chinese Academy of Sciences, and the Chinese National
Human Genome Center at Shanghai, Shanghai, China; Clontech
Laboratories, Palo Alto, CA; the Division of Neoplastic Diseases,
Department of Medicine, Mount Sinai Medical Center, New York, NY; and
Institute National de la Santé et de la Recherche Medicalé
(INSERM) Unité, Hospital Saint Louis, Paris, France.
To elucidate the molecular mechanism of
all-trans-retinoic acid (ATRA)-induced differentiation of
acute promyelocytic leukemia (APL) cells, the gene expression
patterns in the APL cell line NB4 before and after ATRA
treatment were analyzed using complementary DNA array,
suppression-subtractive hybridization, and
differential-display-polymerase chain reaction. A total of 169 genes,
including 8 novel ones, were modulated by ATRA. The ATRA-induced gene
expression profiles were in high accord with the
differentiation and proliferation status of the NB4 cells.
The time courses of their modulation were interesting. Among the 100 up-regulated genes, the induction of expression occurred most
frequently 12-48 hours after ATRA treatment, while 59 of 69 down-regulated genes found their expression suppressed within 8 hours.
The transcriptional regulation of 8 induced and 24 repressed
genes was not blocked by cycloheximide, which suggests that these
genes may be direct targets of the ATRA signaling pathway. A balanced
functional network seemed to emerge, and it formed the foundation of
decreased cellular proliferation, maintenance of cell
viability, increased protein modulation, and promotion of
granulocytic maturation. Several cytosolic signaling pathways,
including JAKs/STAT and MAPK, may also be implicated in the
symphony of differentiation.
(Blood. 2000;96:1496-1504) Acute promyelocytic leukemia (APL) is an
interesting model in the study of human cancer because it is the first
human malignancy that can be effectively treated with a cell
differentiation inducer, all-trans-retinoic acid (ATRA).
During the last decade, it was uncovered that the promyelocytic
leukemia-retinoic acid response- Unlike the RARA-CoR complex, the PML/RARA-CoR complex is more stable
and resistant to physiological ATRA treatment. PML/RARA competes with
RARA for binding to the retinoic acid response elements (RAREs) of
target genes and mediating the transcriptional repression through
histone deacetylation by the CoR complex.7-13
Pharmacological doses of ATRA could trigger the degradation of PML/RARA
and the reassembly of PODs.14 More recently, ATRA has been
shown to cause a distinct conformational change of PML/RARA. This
results in release of the CoR complex and subsequent recruitment of a coactivator (CoA) complex (CBP/P300, P/CAF, NcoA-1/SRC-1, P/CIP, and
ACTR) and converts PML/RARA from transcription repressor to transcription activator. In contrast, the association of CoR with PLZF/RARA, a fusion receptor associated with an APL phenotype resistant
to ATRA, could not be modulated by the ligand, even at very high
concentrations.7-13 These findings further strengthen the
concept that ATRA-induced differentiation is a novel cancer therapy
based on transcriptional regulation.
Although the interaction between ATRA and the aberrant and wild type
RAR-CoR/CoA complexes was largely elucidated, the molecular events
downstream of the RAR complexes were still unclear. Therefore, using
the ATRA-sensitive APL cell line NB415 as an in
vitro model, we undertook a study based on methods allowing relatively large-scale transcriptional expression analysis to identify gene expression patterns in APL cells upon treatment with ATRA. A total of
169 genes, including transcriptional factors, signal transduction modulators, cell cycle promoters and inhibitors, and protein
modulators, were confirmed to be ATRA-modulated and to form a
harmonious network in the course of the ATRA-induced NB4
cell differentiation.
Cell culture
Differential display-PCR
Construction of cDNA libraries using suppression-subtractive hybridization Suppression-subtractive hybridization (SSH) was performed according to the user's manual (Clontech). The FORWARD library for isolating up-regulated genes was obtained by using cDNA of the NB4 cells treated with ATRA for 48 hours as a "tester," while cDNA of untreated NB4 cells was used as a "driver." The REVERSE library for identifying down-regulated genes was constructed by replacing the cDNA of untreated cells as a "tester," while cDNA of NB4 cells treated with ATRA for 48 hours was used as the "driver."Differential screening of subtractive library As indicated by the manufacturer's protocol, 4 × 96 (384) clones from the FORWARD subtracted library were dotted in duplicate on nylon membranes and hybridized with -32P-labeled
unsubtracted cDNA probes (tester and driver) as well as subtracted cDNA
probes (FORWARD and REVERSE) to minimize the false-positive clones
before embarking further confirmation. Genes showing equal
hybridization signals were ruled out, while genes with different
signals or without any signal were further investigated.
cDNA array Membranes with 588 known genes (Clontech) were used, and hybridization was performed according to the manufacturer's recommendations using the RNA from 3 independent sets of ATRA-stimulated NB4 cells at an indicated time-point. The signals were analyzed on Altasvision software (Clontech) and normalized by the signal intensities of housekeeping genes. Only those genes with signal differences of more than 2-fold were considered as modulated.Sequencing and bioinformatics analysis Sequencing reactions were performed on a 9600 Thermal Cycler using the Dye Primer and Dye Terminator Cycle Sequencing Kit (Perkin-Elmer, Foster City, CA). All sequences were searched against GenBank and dbEST databases (version 108) for homology comparison by using the Genetics Computer Group (GCG) program package. The sequences were considered as part of the known genes if they shared 95% or more homology over at least a 100-bp (base pair) DNA sequence on the BLAST search. For those sequences representing previously unknown genes, GenBank and SWISSPROT searches were performed by using BLAST and FASTA. For those ESTs without significant homology, the motif search was carried out using the Blocks database, version 9.0 (http://www.blocks.fhcrc.org).Northern blot analysis, semiquantitative RT-PCR, and real-time quantitative RT-PCR Northern blot analysis was performed as previously described.20 For semiquantitative RT-PCR, G3PDH was used as an internal control with the following primer sets: sense, 5'-TGA AGG TCG GAG TCA ACG GAT TTG GT-3', and antisense, 5'-CAT GTG GGC CAT GAG GTC CAC CAC-3'. G3PDH and gene-specific primers were placed in a single tube. PCR was performed in 20-mL volumes using the Perkin-Elmer Cycler 480 (Perkin-Elmer) at the following conditions: 1 cycle for 5 minutes at 94°C; 20-30 cycles for 45 seconds at 94°C, 45 seconds at 56°C, and 1.5-2 minutes at 72°C. All RT-PCR reactions were repeated at least 3 times at different numbers of the extension cycle to avoid the false results of the PCR. The signals were normalized against 983-bp G3PDH using a densitometer. Triplicate real-time RT-PCR was performed using the ABI PRISM 7700 Sequence Detection System (Perkin-Elmer) with the same RNA templates of semiquantitative RT-PCR. -Actin was coamplified as an endogenous control to standardize the
amount of the sample RNA added to the reaction. The results of the
indicated time-points after the ATRA treatments were plotted relative
to the level at time zero.
Full-length cDNA cloning and sequencing Two methods were used for full-length cDNA cloning: "in silico" cloning and the rapid amplification of the cDNA end (RACE). The in silico cloning started from novel cDNA sequences obtained in the current work, and overlapping dbEST sequences were assembled into contigs to get the open reading frames (ORFs), which were subject to further check by RT-PCR and subsequent sequencing. In RACE, self-made marathon-ready cDNAs were used as templates, and the touchdown PCR reaction was carried out according to the manufacturer's protocol. Candidate bands were cut and cloned into pGEM-T (Promega Company, Madison, WI) or pT-Adv vector (Clontech). The sequences were analyzed for possible ORFs using the Autoassembler and Strider 1.2 program. If necessary, further RACE walking was performed until a complete ORF was obtained.
Identification of the genes modulated by ATRA in NB4 cells Using 3 techniques, a number of genes and cDNA clones were identified as being regulated in NB4 cells after treatment with ATRA for approximately 8-72 hours. Triplicated cDNA array analysis revealed a total of 99 of 588 (16.8%) "hot spot" known genes to be modulated with more than a 2-fold difference of expression levels between ATRA-treated NB4 cells and untreated cells (Figure 1A). Among these 99 genes, 37 presented up-regulated signals, and 62 were down-regulated. The expression of 8 up-regulated genes and 2 down-regulated genes was confirmed by RT-PCR with coherent patterns (data not show). Using DD-PCR, 13 of 30 bands were identified and subsequently confirmed to represent genes with induced expression, while probes prepared from 7 of 30 bands gave signals of equal intensity before and after ATRA treatment, as detected by Northern blot analysis. Using Northern blotting, there were no signals in 10 of 30 bands.
SSH gave rise to a total of 703 clones (660 from FORWARD and 43 from REVERSE). Sequence analysis of these clones led to an assembly of 316 contigs (278 from FORWARD and 38 from REVERSE), of which 159 were known genes; 25 were matched mitochondria DNA, ribosomal RNA, and Alu repeats; and 132 were novel sequence fragments. The 159 known genes were subject to further analysis using differential screening and semiquantitative RT-PCR. Of these 159 genes, 39.6% were confirmed to be modulated (55 induced and 8 repressed), whereas the remainder showed either equal expression patterns or no obvious signals. Among these regulated genes, 10 were further confirmed by Northern blotting, which showed a pattern similar to RT-PCR. All novel sequence fragments were also further examined with differential screening and RT-PCR, and 49 of 132 showed an ATRA-modulated expression. The expression patterns of 3 novel genes were further studied by
real-time quantitative RT-PCR assay, and they turned out to be highly
similar to those from the semiquantitative RT-PCR assay (Figure 1D).
Moreover, 2 methods, in silico cloning (dbEST version 108.0) and RACE,
were carried out to acquire full-length cDNA from novel gene sequences.
The sequences were confirmed by RT-PCR and/or Northern blot
analysis as being modulated by ATRA. Thus, we obtained 8 cDNA
containing putative ORFs according to bioinformatic analysis. Of the 8 cDNA, 5 showed significant homology to known genes with potential
structural and/or functional importance, whereas 3 exhibited only
limited homology to known genes. Table 1
summarizes the major structural features of the 8 novel genes in the
present work, temporarily under the name of RIG (retinoic acid-induced gene), and their nucleic acid sequences, as well as
deduced amino acid sequences, are now available in GenBank.
The overall results obtained using these 3 approaches seemed to be
quite cohesive and complimentary. For example, RIG-E, RIG-G, and dioxin-inducible cytochrome P450 genes initially
discovered by DD-PCR were also found to be up-regulated by SSH, whereas
the induction of 16 genes, such as the monocyte chemoattractant protein (MCP), interleukin-8 (IL-8), the Src-like
adaptor protein, and Bfl-1, were revealed by both cDNA
array and SSH. The advantage of combining the 3 different methods was
based on the concept that each of them might reflect a gene expression
profile from a particular angle. The cDNA array used in this work only
covers 588 known genes. DD-PCR generates a partial view of gene
expression, while SSH may allow a more global approach for
identification of both known and novel genes, although the efficiency
of the method (in this work, 38.5%) needs to be further improved.
After integration of the results by different techniques, a total of 169 genes were identified as ATRA-responsive, including 100 up-regulated and 69 down-regulated genes (Figure
2A-J).
Functional categories of genes regulated by ATRA The 100 up-regulated and 69 down-regulated genes by ATRA were classified into 10 categories according to their structures and/or functions (Figure 2A-J). Some transcription factors, such as c-JUN, ETR, ID-2, HOX-A1, and CEBP , were found
to be induced. Interestingly, one component of CoA,
ACTR,21 was also included in this group as a
relatively early induced gene (12 hours). Genes participating in
several important signal transduction pathways, including JAKs/STAT,
cAMP/PKA, PKC, and calmodulin, were modulated. Other notable categories
of genes included those responsible for protein modulation, such as
UAE122 and SUMO-123; for
apoptosis resistance, DAD-1,24
Bfl-1,25 and GADD15326;
and p19INK4d and
p21WAF1/CIP1 for cell cycle
exit.27,28 A number of genes reported to possess the
function of proliferation suppression, including
BTG1,29 Src-like adaptor
protein,30 FGR,31 and
LIMK,32 were also positively modified. The
induced expression of some neutrophil function-related genes (eg,
MCP-1,33 defensin, and X-CGD) may reflect biological activities needed in terminal granulocytic differentiation.
On the other hand, 69 down-regulated genes could be of functional
importance in terms of cell growth regulation. Transcription factors
known to be capable of promoting cell proliferation, including c-MYC, NF Identification of possible direct target genes of ATRA We tried to find the genes whose transcriptional regulation was protein synthesis-independent and thus most likely represented target genes of RA receptors. By using the cycloheximide inhibition test, the response of 8 up-regulated genes to ATRA was not abolished by protein synthesis antagonist. That all these genes were up-regulated at an early stage (within 12 hours) was also in support of their direct induction by RA receptors. Among these 8 cycloheximide-resistant up-regulated genes, one of them is CEBP, which has been
confirmed by other groups to be very important for the initiation of
granulocytic differentiation.37-39 Cell cycle inhibitor
p21WAF1/CIP1, apoptosis antagonists
Bcl-2-related (Bfl-1) and GADD153
(CHOP), and some receptors and membrane proteins
(RIG-E, ICAM-1, and CD52) were also
confirmed to be in this group. Surprisingly, the transcriptional modulation in 24 of 69 down-regulated genes appeared not to be inhibited by cycloheximide, and the onset of their down-regulation all
occurred within 8 hours after treatment with ATRA (Figure 2A-J).
Gene expression waves in concert with APL cell differentiation To receive insight into the gene expression network modulated by ATRA, it is important not only to obtain the gene catalog in the network but also to clarify the time course of the transcriptional regulation in each of the modulated genes. To this end, a better definition of the phenotypic changes of NB4 cells upon ATRA, with regard to time course, was necessary. At the early time-points (8 and 12 hours) of the ATRA treatment, there were no obvious morphological changes in the NB4 cells (Figure 3). The percentages of CD11b+ cells were still at the same level as that of time zero. PML/RARA degradation was not yet distinct. However, the increase of the G0/G1-phase cells and decrease of the S-phase cells were concomitant with the depression of cell proliferation that was started prior to 8 hours of ATRA treatment. After 24 hours of ATRA treatment, the differentiation markers of the NB4 cells began to be observable. CD11b+ and NBT+ cells gradually increased from 24-72 hours after treatment. The ratio of cytoplasm to nucleus was increased, and the chromatin condensation occurred gradually. There was no evident apoptosis observed during the whole course of the treatment. Meanwhile, PML/RARA degradation could be readily observed. Therefore, the time course of differentiation could be roughly divided into 2 phases: before 12 hours and after 12 hours of treatment.
In agreement with the above observation, the expression patterns of the 169 genes were studied using the cDNA array, semiquantitative RT-PCR, and/or Northern blot analysis on NB4 cells prior to ATRA treatment and at 8, 12, 24, 48, and 72 hours after treatment (Figure 1B,C). (For some genes, Northern blot analysis was performed as early as 4 hours.) Among the 100 genes with up-regulated expression, 53 genes (53%) were induced within 12 hours, 46 genes (46%) were induced between 24 and 48 hours, and only 1 gene was induced after 72 hours. In contrast, the modulation patterns of the 69 down-regulated genes were quite different because the expression level in 59 genes rapidly declined 8 hours after ATRA treatment, and the expression was suppressed in only 10 genes after 12 hours. Of note, 9 genes suppressed early by ATRA treatment showed increased expression or were restored to basal expression at a late stage (Figure 2 A-J). The time course of the regulated gene expression patterns was highly
associated with the differentiation status of NB4 cells. Genes modulated before 12 hours (such as CEBP
During the last few years, we and several other groups have isolated, in a piecemeal way, RA-regulated genes during ATRA-triggered granulocytic differentiation.1 However, there was no systematic survey of gene expression regulation upon the effect of ATRA, and few genes were known to be direct targets of RA in APL cells. Only recently have innovative tools, such as cDNA microarray, allowed a more global approach of the analysis of transcriptional regulation including regulation in APL cells.40 In the present work, which applied several new techniques, 100 genes, including 8 novel ones, were found to be up-regulated by ATRA, while 69 genes were down-regulated. A total of 169 genes were regulated by ATRA, and they may represent approximately 0.8%-1.7% of all genes expressed in APL cells (if the estimation that about 10 000-20 000 genes are expressed in a given cell type holds).41 There are some overlaps between our results and those of Tamayo et al,40 whose group used Affymetrix chips to profile the transcriptional response of NB4 cells to ATRA. A total of 48 up-regulated and 39 down-regulated genes in our system were also included in the system described by Tamayo et al.40 In addition, 42 of 48 up-regulated genes and 20 of 39 down-regulated genes were found to have similar expression patterns in both systems, which suggests a relatively good overall agreement (73.6%) between the results of these 2 groups with different technical approaches. However, 4 of 48 up-regulated genes and 15 of 39 down-regulated genes picked up in our system were not found to be modulated in the system of Tamayo et al. Moreover, the modulation patterns of 6 genes were contradictory between the 2 systems. It is worth pointing out that for the 2 up-regulated genes with a discrepancy (CD11A and LIMK1), our results of cDNA array were confirmed by RT-PCR. There could be several reasons to explain these differences. Because all genes with disparate results were those with only 2-fold to 5-fold modulation, we deduce that the difference could be caused by distinct sensitivities of the analysis systems employed. Another possibility is that NB4 cells in different laboratories could be subject to slightly distinct culture conditions, which could affect expression of some of the genes. When RA-modulated genes were analyzed for their functions, a
picture of well-coordinated choreography emerged, and this may reflect
an elegant and intricate cellular program for the commitment to
differentiation. For example, many studies suggested that the initiation of differentiation required the transcriptional activation of specific genes leading to proliferation arrest and cell cycle exit.
Supporting this notion, indeed, a number of genes known to be able to
suppress proliferation and cell cycle progress, such as
p21WAF1/CIP1,
p19INK4D, GADD153, BTG1,
and the Src-like adaptor protein, were up-regulated. Along
these same lines, genes favoring DNA synthesis and/or repair and
G1-S/G2-M transition, such as c-MYC, c-MYB,
GATA2, XRCC1, P55CDC, cyclin
A, and cyclin B1, were down-regulated early during ATRA
treatment. Another example could be the balance between apoptosis and
differentiation. It can be postulated that the apoptosis process, which
was favored by the degradation of PML/RARA and the release of
PMLs,5,42 should be temporarily inhibited in
NB4 cells until the terminal differentiation occurs. Of
note, several apoptosis antagonists, such as Bcl-2-related
(A1) and DAD1, were up-regulated. Moreover, FGR
protein-tyrosine kinase, which had been demonstrated to promote
RA-induced granulocytic differentiation of HL-60 cells by preventing
programmed cell death, had also been induced.31 Hence,
modulated expression of these genes seems to offer a survival signal as
an essential prerequisite for the cell maturation process (Figure
4). It is a well-established fact that a
few transcription factors play important roles in RA signal pathways.
The over-expression of these genes could lead cells into
differentiation. It is interesting to detect the up-regulation of one
of them, namely CEBP
A previous study23 indicated that POD reorganization represented an immediate consequence of PML/RARA degradation, which could be inhibited by lactacystin, a specific inhibitor of proteasome.14 To this end, it is worth noting that 2 enzymes implicated in the step-wise catalysis of binding the ubiquitin polymer to the target protein, the ubiquitin-activating enzyme E1 (UAEE1) and ubiquitin-conjugating enzyme (UCE) genes,22 were up-regulated at 8 hours and 24 hours, respectively, after ATRA treatment. SUMO-1, which encodes a ubiquitin-like protein reportedly to be involved in PML relocalization,23 was induced after 4 hours of ATRA treatment. Interestingly, 2 novel genes isolated in the present work, RIG-A and RIG-B, share, respectively, 55% and 92% amino acid identities with the mouse ubiquitin-conjugating enzyme and cattle leucine aminopeptidase. This suggests that they may also be implicated in the regulation of protein modification. To distinguish genes as the direct targets of ATRA and as those regulated by the protein products of the direct targets will lead to the dissection of different gene expression "waves" during cell differentiation. The cycloheximide inhibition test suggested that 8 up-regulated genes could be direct targets of RA receptors (Figure 2). The presence of RARE at the promoter regions in 3 up-regulated genes with available 5'-flanking sequences, namely RIG-E (M.M. and Z.C., unpublished data, August 1998), ICAM-1,43 and p21WAF1/CIP1,44 is in agreement with the current model of ligand-dependent control of the RA receptor activity. In various models of differentiation, the induction of p21WAF1/CIP1 appeared to be essentially required for the G1-S-phase arrest.45,46 One could therefore image that p21WAF1/CIP1 may act in the upstream of the differentiation course (Figure 4). The puzzle that 24 genes seem to be down-regulated with no requirement for protein synthesis represents a challenge to the current model, which has no explanation for the ligand-dependent transcriptional repression. Several working hypotheses could, nevertheless, be proposed. First, there could be a general competition mechanism for the binding of transcription factors to CoA or CoR molecules.47 Second, the release of wild type PML and PLZF, which were both found to be sequestered by PML/RARA, could restore their function as growth suppressors. Of note, PLZF has been shown to repress the expression of the cyclin A gene.35 Third, there could be an opposition between the effects of RA signaling and AP-1.48-50 It is worth mentioning that the promoter regions of some of the ATRA down-regulated genes, such as TF and DNA (cytosin-5)-methyltransferase, contain AP-1 sites.51,52 The significance of cross-talk or coupling between nuclear and cytosolic signalings in APL cell differentiation has recently drawn much attention. In this work, we found that a number of genes encoding molecules involved in important cytosolic signal transduction pathways were modulated by ATRA. These include cytosolic kinase signal transducers such as cytokine receptors STATs/ISGs, cAMP/PKA, and MAPK/P38/JNK. The functions of the 2 novel genes, RIG-C and RIG-D, should be further studied because they share, respectively, 92.6% and 79% amino acid identities with mouse WSB-1 and hematopoietic intracellular protein tyrosine phosphatase, both being important regulators in signal transduction.53,54 In conclusion, by applying large-scale screening of the differentially expressed genes during ATRA-induced APL cell differentiation, we identified 169 modulated genes, which could be divided into 10 functional groups. A model of gene regulatory network during this process was thus obtained and provided precious datasets for further work to ultimately clarify the mechanism of APL leukemogenesis and ATRA-induced differentiation.
The authors thank J. Gu for constructive discussion and Q. H. Huang, J. Zhou, P. M. Jia, Y. P. Yu, and S. H. Xu for excellent technical assistance.
Submitted September 2, 1999; accepted April 7, 2000.
Supported in part by the Chinese High Tech Program 863 (grant no. Z19-02-01-02); the National Natural Sciences Foundation of China (grant no. 39830170); the Shanghai Life Science Center and the Clyde Wu Foundation of the Shanghai Institute of Hematology, Shanghai, China; and the Samuel Waxman Cancer Research Foundation.
T.-X.L., J.-W.Z., and J.T. contributed equally to this work.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Zhu Chen, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Second Medical University, 197 Rui Jin Road II, 200025, Shanghai, China; e-mail: mbshi{at}stn.sh.cn.
1.
Ari M, Jonathan DL.
Deconstructing a disease: RAR 2. Dyck JA, Maul GG, Miller WH, Chen JD, Kakizuka A, Evans RD. A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein. Cell. 1994;76:333[Medline] [Order article via Infotrieve].
3.
Mu ZM, Chin KV, Liu JH, Lozano G, Chang KS.
PML, a growth suppressor disrupted in acute promyelocytic leukemia.
Mol Cell Biol.
1994;14:6858
4.
Wang ZG, Delva L, Gaboli M, et al.
Role of PML in cell growth and the retinoic acid pathway.
Science.
1998;279:1547 5. Wang ZG, Ruggero D, Ronchetti S, et al. PML is essential for multiple apoptotic pathways. Nat Genet. 1998;20:266[Medline] [Order article via Infotrieve].
6.
Kastner P, Perez A, Lutz Y, et al.
Structure, localisation and transcriptional properties of two classes of retinoic acid receptor
7.
Hong SH, David G, Wong CW, Dejean A, Privalsky ML.
SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor 8. Lin RJ, Nagy L, Inoue S, Shao W, Miller WH Jr, Evans RM. Role of the histone deacetylase complex in acute promyelocytic leukemia. Nature. 1998;391:811[Medline] [Order article via Infotrieve].
9.
Grignani F, De Matteis S, Nervi C, et al.
Fusion proteins of the retinoic acid receptor-
10.
Collins SJ.
Acute promyelocytic leukemia: relieving repression induces remission.
Blood.
1998;91:2631
11.
Guidez F, Ivins S, Zhu J, Soderstrom M, Waxman S, Zelent A.
Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML and RAR
12.
He LZ, Guidez F, Tribioli C, et al.
Distinct interaction of PML-RAR
13.
Cheng GX, Zhu XH, Men XQ, et al.
Distinct leukemia phenotypes in transgenic mice and different corepressor interactions generated by promyelocytic leukemia variant fusion genes PLZF-RAR
14.
Yoshida H, Kitamura K, Tanaka K, et al.
Accelerated degradation of PML-retinoic acid receptor
15.
Lanotte M, Martin-Thouvenin V, Najman S, Balerini P, Valensi F, Berger R.
NB4, a maturation inducible cell line with t(15;17) marker isolated from a human acute promyelocytic leukemia (M3).
Blood.
1991;77:1080 16. Duprez E, Ruchaud S, Houge GA, et al. A retinoid acid 'resistant' t(15;17) acute promyelocytic leukemia cell line: isolation, morphological, immunological, and molecular features. Leukemia. 1992;6:1281[Medline] [Order article via Infotrieve]. 17. Makishima M, Honma Y. Ethacrynic acid and 1a, 25-dihydroxyvitamin D3 cooperatively inhibit proliferation and induce differentiation of human myeloid leukemia cells. Leuk Res. 1996;20:781[Medline] [Order article via Infotrieve].
18.
Takuma T, Takeda K, Konno K.
Synergism of tumor necrosis factor and interferon-
19.
Kanatani Y, Kasukabe T, Okabe-Kado J, et al.
Transforming growth factor
20.
Mao M, Yu M, Tong JH, et al.
RIG-E, a human homolog of the murine Ly-6 family, is induced by retinoic acid during the differentiation of acute promyelocytic leukemia.
Proc Natl Acad Sci U S A.
1996;93:5910 21. Chen H, Lin RJ, Schiltz RL, et al. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell. 1997;90:569[Medline] [Order article via Infotrieve]. 22. Mark H. Ubiquitin, proteasomes, and the regulation of intracellular protein degradation. Curr Opin Cell Biol. 1995;7:215[Medline] [Order article via Infotrieve]. 23. Müller S, Matunis MJ, Dejean A. Conjugating with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus. EMBO J. 1998;17:61[Medline] [Order article via Infotrieve]. 24. Sugimoto A, Hozak RR, Nakashima T, Nishimoto T, Rothman JH. Dad-1, an endogenous programmed cell death suppressor in Caenorhabditis elegans and vertebrates. EMBO J. 1995;14:4434[Medline] [Order article via Infotrieve].
25.
Zong WX, Edelstein LC, Chen C, Bash J, Gelinas C.
The prosurvival bcl-2 homolog bfl-1/A1 is a direct transcriptional target of NF-kappa B that blocks TNFalpha-induced apoptosis.
Genes Dev.
1999;13:382 26. Eymin B, Dubrez L, Allouche M, Solary E. Increased GADD153 messenger RNA level is associated with apoptosis in human leukemic cells treated with etoposide. Cancer Res. 1997;5:686. 27. Luh FY, Archer SJ, Domaille PJ, et al. Structure of the cyclin-dependent kinase inhibitor p19Ink4d. Nature. 1997;389:999[Medline] [Order article via Infotrieve]. 28. Asada M, Yamada T, Ichijo H, et al. Apoptosis inhibitory activity of cytoplasmic p21(Cip1/WAF1) in monocytic differentiation. EMBO J. 1999;18:1223[Medline] [Order article via Infotrieve]. 29. Rouault JP, Rimonkh R, Tessa C, et al. BTG1, a member of a new family of antiproliferative genes. EMBO J. 1992;11:1663[Medline] [Order article via Infotrieve]. 30. Roche S, Alonso G, Kazlauskas A, Dixit VM, Courtneidge SA, Pandey A. Src-like adaptor protein (Slap) is a negative regulator of mitogenesis. Curr Biol. 1998;8:975[Medline] [Order article via Infotrieve].
31.
Koko K, Kazunari KY, Tadashi Y, Satoshi Ö.
Lyn and Fgr protein-tyrosine kinases prevent apoptosis during retinoic acid-induced granulocytic differentiation of HL-60 cells.
J Biol Chem.
1996;271:11557 32. Higuchi O, Baeg GH, Akiyama T, Mizuno K. Suppression of fibroblast cell growth by overexpression of LIM-kinase 1. FEBS Lett. 1996;396:81[Medline] [Order article via Infotrieve].
33.
Burn TC, Petrovick MS, Hohans S, Rollins BJ, Tenen DG.
Monocyte chemo-attractant protein-1 gene is expressed in activated neutrophils and retinoic acid-induced human myeloid cell lines.
Blood.
1994;84:2776
34.
Tsai FY, Orkin SH.
Transcription factor GATA-2 is required for proliferation/survival of early hematopoietic cells and mast cell formation, but not for erythroid and myeloid terminal differentiation.
Blood.
1997;89:3636 35. Yeyati PL, Shaknovich R, Boterashvili S, et al. Leukemia translocation protein PLZF inhibits cell growth and expression of cyclin A. Oncogene. 1999;18:925[Medline] [Order article via Infotrieve].
36.
Innocente SA, Abrahamson JL, Cogswell JP, Lee JM.
P53 regulates a G2 checkpoint through cyclin B1.
Proc Natl Acad Sci U S A.
1999;96:2147
37.
Morosetti R.
A novel, myeloid transcription factor, C/EBP epsilon, is upregulated during granulocytic, but not monocytic, differentiation.
Blood.
1997;90:2591
38.
Lekstrom-Himes JA, Dorman SE, Kopar P, Holland SM, Gallin J.
Neutrophil-specific granule deficiency results from a novel mutation with loss of function of the transcription factor CCAAT/enhancer binding protein epsilon.
J Exp Med.
1999;189:1847 39. Park DJ, Chumakov AM, Vuong PT, et al. CCAAT/enhancer binding protein epsilon is a potential retinoid target gene in acute promyelocytic leukemia treatment. J Clin Invest. 1999;103:1399[Medline] [Order article via Infotrieve].
40.
Tamayo P, Slonim D, Mesirov J, et al.
Interpreting patterns of gene expression with self-organizing maps: methods and application to hematopoietic differentiation.
Proc Natl Acad Sci U S A.
1999;96:2907 41. Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD. Molecular Biology of the Cell. New York: Garland Publishing, Inc; 1994:368.
42.
Nason-Burchenal K, Takle G, Pace U, et al.
Targeting the PML/RAR 43. Cilenti L, Toniato E, Ruggiero P, et al. Transcriptional modulation of the human intercellular adhesion molecule gene I (ICAM-1) by retinoic acid in melanoma cells. Exp Cell Res. 1995;218:263[Medline] [Order article via Infotrieve].
44.
Liu M, Iavarone A, Freedman LP.
Transcriptional activation of the human P21WAF1/CIP1 gene by retinoic acid receptor: correlation with retinoid induction of U937 cell differentiation.
J Biol Chem.
1996;271:31723 45. Kenneth W, Harris P. Cell cycle exit upon myogenic differentiation. Curr Opin Genet Dev. 1997;7:597[Medline] [Order article via Infotrieve].
46.
Steinman RA, Huang JP, Yaroslavskiy B, Goff JP, Ball ED, Nguyen A.
Regulation of P21(WAF1) expression during normal myeloid differentiation.
Blood.
1998;91:4531
47.
Korzus E, Torchia J, Rose DW, et al.
Transcriptional factor-specific requirements for coactivators and their acetyltransferase functions.
Science.
1998;279:703
48.
Caelles C, Gonzalez-Sancho JM, Munoz A.
Nuclear hormone receptor antagonism with AP-1 by inhibition of the JNK pathway.
Genes Dev.
1997;11:3351 49. Vallian S, Gäken JA, Gingold EB, Kouzarides T, Chang KS. Modulation of Fos-mediated AP-1 transcription by the promyelocytic leukemia protein. Oncogene. 1998;16:2843[Medline] [Order article via Infotrieve].
50.
Lee HY, Walsh GL, Dawson MI, Hong WK, Kurie JM.
All-trans retinoic acid inhibits Jun N-terminal kinase-dependent signaling pathways.
J Biol Chem.
1998;273:7066 51. Felts SJ, Stoflet ES, Eggers CT, Getz MJ. Tissue factor gene transcription in serum-stimulated fibroblasts is mediated by recruitment of c-Fos into specific AP-1 DNA-binding complexes. Biochemistry. 1995;34:12355[Medline] [Order article via Infotrieve].
52.
Bakin AV, Curran T.
Role of DNA 5-methylcytosine transferase in cell transformation by fos.
Science.
1999;283:387
53.
Matthews RJ, Bowne DB, Flores E, Thomas ML.
Characterization of hematopoietic intracellular protein tyrosine phosphatases: description of a phosphatase containing an SH2 domain and another enriched in proline-, glutamic acid-, serine-, and threonine-rich sequences.
Mol Cell Biol.
1992;12:2396
54.
Hilton DJ, Richardson RT, Alexander WS, et al.
Twenty proteins containing a C-terminal SOCS box form five structural classes.
Proc Natl Acad Sci U S A.
1998;95:114
© 2000 by The American Society of Hematology.
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  M. Wall, G. Poortinga, K. M. Hannan, R. B. Pearson, R. D. Hannan, and G. A. McArthur Translational control of c-MYC by rapamycin promotes terminal myeloid differentiation Blood, September 15, 2008; 112(6): 2305 - 2317. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N.-N. Zhang, S.-H. Shen, L.-J. Jiang, W. Zhang, H.-X. Zhang, Y.-P. Sun, X.-Y. Li, Q.-H. Huang, B.-X. Ge, S.-J. Chen, et al. RIG-I plays a critical role in negatively regulating granulocytic proliferation PNAS, July 29, 2008; 105(30): 10553 - 10558. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-Y. Wang and Z. Chen Acute promyelocytic leukemia: from highly fatal to highly curable Blood, March 1, 2008; 111(5): 2505 - 2515. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. B. Miranda, R. L. Redner, and D. E. Johnson Inhibition of Src family kinases enhances retinoic acid induced gene expression and myeloid differentiation Mol. Cancer Ther., December 1, 2007; 6(12): 3081 - 3090. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-S. Liu, X.-H. Li, Y. Wang, R.-Z. Shu, L. Wang, S.-Y. Lu, H. Kong, Y.-E Jin, L.-J. Zhang, J. Fei, et al. Disruption of palladin leads to defects in definitive erythropoiesis by interfering with erythroblastic island formation in mouse fetal liver Blood, August 1, 2007; 110(3): 870 - 876. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Khanna-Gupta and N. Berliner ATRA: Finding targeted APL therapy targets Blood, July 15, 2007; 110(2): 476 - 477. [Full Text] [PDF]
|
|
|
|
|
|
H. Hattori, X. Zhang, Y. Jia, K. K. Subramanian, H. Jo, F. Loison, P. E. Newburger, and H. R. Luo RNAi screen identifies UBE2D3 as a mediator of all-trans retinoic acid-induced cell growth arrest in human acute promyelocytic NB4 cells Blood, July 15, 2007; 110(2): 640 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G.-B. Zhou, J. Zhang, Z.-Y. Wang, S.-J. Chen, and Z. Chen Treatment of acute promyelocytic leukaemia with all-trans retinoic acid and arsenic trioxide: a paradigm of synergistic molecular targeting therapy Phil Trans R Soc B, June 29, 2007; 362(1482): 959 - 971. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Rasooly, G. U. Schuster, J. P. Gregg, J.-H. Xiao, R. A. S. Chandraratna, and C. B. Stephensen Retinoid X Receptor Agonists Increase Bcl2a1 Expression and Decrease Apoptosis of Naive T Lymphocytes J. Immunol., December 15, 2005; 175(12): 7916 - 7929. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Segara, A. V. Biankin, J. G. Kench, C. C. Langusch, A. C. Dawson, D. A. Skalicky, D. C. Gotley, M. J. Coleman, R. L. Sutherland, and S. M. Henshall Expression of HOXB2, a Retinoic Acid Signaling Target in Pancreatic Cancer and Pancreatic Intraepithelial Neoplasia Clin. Cancer Res., May 1, 2005; 11(9): 3587 - 3596. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Glasow, N. Prodromou, K. Xu, M. von Lindern, and A. Zelent Retinoids and myelomonocytic growth factors cooperatively activate RARA and induce human myeloid leukemia cell differentiation via MAP kinase pathways Blood, January 1, 2005; 105(1): 341 - 349. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
 |
|
 S. Tsuzuki, K. Kitajima, T. Nakano, A. Glasow, A. Zelent, and T. Enver Cross Talk between Retinoic Acid Signaling and Transcription Factor GATA-2 Mol. Cell. Biol., August 1, 2004; 24(15): 6824 - 6836. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-J. Kim and R. Lotan Identification of Retinoid-Modulated Proteins in Squamous Carcinoma Cells Using High-Throughput Immunoblotting Cancer Res., April 1, 2004; 64(7): 2439 - 2448. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Klausen, M. D. Bjerregaard, N. Borregaard, and J. B. Cowland End-stage differentiation of neutrophil granulocytes in vivo is accompanied by up-regulation of p27kip1 and down-regulation of CDK2, CDK4, and CDK6 J. Leukoc. Biol., March 1, 2004; 75(3): 569 - 578. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. T. Dorsam, C. M. Ferrell, G. P. Dorsam, M. K. Derynck, U. Vijapurkar, D. Khodabakhsh, B. Pau, H. Bernstein, C. M. Haqq, C. Largman, et al. The transcriptome of the leukemogenic homeoprotein HOXA9 in human hematopoietic cells Blood, March 1, 2004; 103(5): 1676 - 1684. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Inagaki, S. Suzuki, T. Miyamoto, T. Takeda, K. Yamashita, A. Komatsu, K. Yamauchi, and K. Hashizume The Retinoic Acid-responsive Proline-rich Protein Is Identified in Promyeloleukemic HL-60 Cells J. Biol. Chem., December 19, 2003; 278(51): 51685 - 51692. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
 |
|
 Z.-y. Wang Ham-Wasserman Lecture: Treatment of Acute Leukemia by Inducing Differentiation and Apoptosis Hematology, January 1, 2003; 2003(1): 1 - 13. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
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|
Y. Jing, L. Xia, and S. Waxman Targeted removal of PML-RARalpha protein is required prior to inhibition of histone deacetylase for overcoming all-trans retinoic acid differentiation resistance in acute promyelocytic leukemia Blood, July 18, 2002; 100(3): 1008 - 1013. [Abstract] [Full Text] [PDF]
|
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|
|
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|
 J. L. Slack, S. Waxman, G. Tricot, M. S. Tallman, and C. D. Bloomfield Advances in the Management of Acute Promyelocytic Leukemia and Other Hematologic Malignancies with Arsenic Trioxide Oncologist, April 1, 2002; 7(90001): 1 - 13. [Abstract] [Full Text] [PDF]
|
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A. Wallqvist, A. A. Rabow, R. H. Shoemaker, E. A. Sausville, and D. G. Covell Establishing Connections between Microarray Expression Data and Chemotherapeutic Cancer Pharmacology Mol. Cancer Ther., March 1, 2002; 1(5): 311 - 320. [Abstract] [Full Text] [PDF]
|
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C. Moog-Lutz, E. J. Peterson, P. G. Lutz, S. Eliason, F. Cave-Riant, A. Singer, Y. Di Gioia, S. Dmowski, J. Kamens, Y. E. Cayre, et al. PRAM-1 Is a Novel Adaptor Protein Regulated by Retinoic Acid (RA) and Promyelocytic Leukemia (PML)-RA Receptor alpha in Acute Promyelocytic Leukemia Cells J. Biol. Chem., June 15, 2001; 276(25): 22375 - 22381. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
B, and GATA2,
in induction of differentiation of human myeloblastic leukemic ML-1 cells.
Biochem Biophys Res Commun.
1987;145:514