Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Spotlight on Acute Promyelocytic Leukemia

The role of retinoids and retinoic acid receptors in normal hematopoiesis

Abstract

The dramatic therapeutic activity of all-trans retinoic acid (ATRA) in inducing terminal granulocytic differentiation of the malignant promyelocytes that characterize human acute promyelocytic leukemia (APL) has led to numerous studies assessing the role of retinoids and the retinoic acid receptors (RARs) in the regulation of normal hematopoiesis. Studies with knock out mice indicate that retinoic acid receptor activity is not essential for normal hematopoiesis, but both in vitro and in vivo studies indicate that these receptors may be important modifiers/regulators of different myeloid precursors/ progenitors including the primitive transplantable stem cell. A number of target genes have been identified that are either directly or indirectly regulated by RA receptors and which likely play important roles in the retinoid-mediated regulation of myelopoiesis. Several in vitro models of hematopoiesis suggest that the transcriptional activity of RA receptors is developmentally regulated during different stages of myelopoiesis. This regulation might involve non-ligand mediated molecular events that alter the interaction of RA receptors with transcriptional corepressor complexes. Moreover, the interaction of RA receptors with other families of transcription factors expressed in different hematopoietic lineages might also account for differential RA receptor activity at different stages of myelopoiesis.

Introduction

The retinoic acid receptors, which include two distinct families, the RARs and RXRs are important regulators of embryonic development and also influence the growth and differentiation of adult cell types. In human acute promyelocytic leukemia (APL) there is a block to normal granulocytic differentiation which, if untreated, results in the lethal accumulation of immature promyelocytes. Virtually all cases of APL are characterized by the presence of a chromosome translocation involving the retinoic acid receptor alpha (RARα) gene on chromosome 17.1,2,3,4,5 The most common of these chromosome translocations, t(15;17) generates the PML-RARα fusion protein that inhibits the function of normal RARs.6,7,8 The block to granulocytic differentiation in APL is overcome by high ‘pharmacological’ concentrations of all-trans retinoic acid (ATRA) which likely accounts for the marked therapeutic effect of ATRA in human APL.9,10,11,12 In addition transduction of a COOH-terminal truncated RARα harboring dominant negative activity into normal mouse bone marrow generates hematopoietic growth factor dependent cells frozen at distinct stages of myeloid differentiation. These include the GM-CSF-dependent MPRO cells, which consist largely of promyelocytes which can be induced to terminally differentiate to granulocytes with high concentrations of ATRA.13 Together these observations suggest that the RARα gene might normally be involved in regulating granulopoiesis, particularly the terminal differentiation of granulocytes. Here we review pertinent studies that utilize a variety of different in vitro and in vivo experimental models to determine the role that retinoic acid and the retinoic acid receptors (particularly RARα) play in regulating myeloid differentiation

Retinoic acid receptors and myelopoiesis – in vitro models

The dramatic therapeutic activity of ATRA in inducing the terminal granulocytic differentiation of malignant promyelocytes has prompted studies determining what role retinoic acid and retinoic acid receptors might play in regulating normal myelopoiesis. Many of these studies compare the behavior of primitive hematopoietic progenitors cultured in the presence or absence of exogenous ATRA. The target cells for these studies have included normal bone marrow or fetal liver mononuclear cells or more highly purified CD34+ or lin-c-kit+Sca-1+ primitive hematopoietic precursors. In these studies the effect of all-trans retinoic acid (ATRA) on the growth and differentiation of these hematopoietic progenitors has included studies both in liquid suspension culture and in semi-solid media (agar or methylcellulose). In general, these studies have suggested a role of ATRA in enhancing the growth and differentiation of granulocyte progenitors.

The effect of ATRA on semi-solid cultures of hematopoietic precursors

A number of different studies have indicated that in semi-solid medium retinoic acid enhances the clonal growth of GM-CSF-dependent colonies derived from normal human bone marrow.14,15,16,17,18 This enhanced myeloid colony growth was observed with both ATRA and 9-cis retinoic acid.17 In multiple studies it has been observed that this ATRA-mediated enhancement of granulocyte progenitor growth and differentiation is associated with decreased production of colonies representing other hematopoietic lineages including erythroid (BFU-E),19,20,21 macrophage,18 mixed granulocyte/macrophage22 and primitive colonies with multipotent potential (HPPs).21 These latter observations suggest that retinoic acid and retinoic acid receptors might be involved in regulating lineage determination by multipotential hematopoietic progenitors. Consistent with this hypothesis are observations utilizing cytokine-dependent cell lines representing multipotential progenitors that continuously proliferate in liquid suspension. For example, the IL-3-dependent FDCPmixA4 cells harbor mixed lineage potential. GM-CSF induces these cells to undergo granulocytic differentiation, while erythropoietin induces their erythroid differentiation.23,24 Selective RARα agonists enhance the myelomonocytic differentiation of the FDCPmixA4 cells, and this is associated with their enhanced RARα expression.25 Conversely RARα antagonists, which are synthetic retinoids that bind to RA receptors with high affinity, but do not activate transcription and thus act as competitive inhibitors of RAR activation,26,27 enhance the erythroid differentiation of these cells while suppressing their myelomonocytic differentiation.25 Similarly IL-3 enhances the commitment of the multipotential, stem cell factor (SCF)-dependent EML cells to the granulocyte/monocyte lineage,28 and this commitment is enhanced by ATRA and inhibited by RAR antagonists.28,29,30 Thus the observed retinoid-induced enhancement of granulocyte colony formation in cultures of normal bone marrow may reflect a role of activated RA receptors in mediating the lineage commitment of multipotential cells to the granulocyte lineage.

Interestingly, the effect of retinoids on the growth of myeloid progenitors is highly selective for the cytokines utilized in the culture system. In studies utilizing normal mononuclear bone marrow cells or purified CD34+ hematopoietic precursors, ATRA, when added to clonogenic cultures in semi-solid media, enhanced the generation of IL-3- and GM-CSF-dependent colonies but had no effect or inhibited G-CSF-dependent colonies.14,31,32 Since G-CSF-dependent colonies likely arise from more mature progenitors than either IL-3- or GM-CSF-dependent colonies, this suggests that ATRA may regulate the proliferation/differentiation of cells at a relatively early stage of myeloid maturation.33

The effect of ATRA on liquid suspension cultures of hematopoietic precursors

The above studies that involve primary hematopoietic cells (rather than cultured cell lines) describe the effect of ATRA on the growth and differentiation of cells cultured in semi-solid media. The effect of exogenous ATRA on the behavior of primitive hematopoietic precursors cultured in liquid suspension in cytokine ‘cocktails’ has also been assessed. These studies also reveal an ATRA-mediated enhancement of GM-CSF-dependent colonies (CFU-GM) in cultures of highly enriched murine hematopoietic precursors (linc-kit+Sca-1+).34 Again ATRA appears to act on a relatively early hematopoietic precursor because enhanced CFU-GM production is not observed in ATRA-treated liquid suspension cultures of more mature precursors (linc-kit+Sca-1).34 Further evidence that ATRA regulates relatively immature precursors in liquid suspension culture is provided by observations that ATRA enhances the mitogenic activity of CD34+ cells,35 generates enhanced numbers of blasts and immature myeloid cells in cultures of linSca-1+ progenitors36 and enhances the generation of CFU-S and both short- and long-term repopulating cells in cultures of linc-kit+Sca-1+ precursors,34 as well as enhancing their serial transplant potential.37 Moreover, an RAR antagonist when added to liquid suspension cultures of linc-kit+Sca-1+ precursors markedly inhibits the generation of repopulating stem cells in such cultures.34 Together these observations suggest that in liquid suspension culture ATRA not only enhances the generation of committed myeloid progenitors but also increases the production of more primitive hematopoietic precursors including CFU-S and both short- and long-term marrow repopulating cells.

The cell/cell interaction in hematopoietic stem cell liquid cultures containing multiple cytokines is likely to be intricate and complex, perhaps involving positive or negative feedback loops influencing stem cell self renewal and/or survival. Indeed it is presently unclear whether the observed effect of ATRA in enhancing the maintenance and/or production of transplantable hematopoietic stem cells in liquid suspension culture results from a direct effect of ATRA on the stem cells or an indirect effect through ‘accessory’ cells that may regulate stem cell activity in such cultures.34 Nevertheless, these observations suggest that ATRA might be clinically utilized to expand the number of hematopoietic stem cells in ex vivo cultures of primitive hematopoietic precursors and/or to aid in retroviral- or lentiviral-mediated gene transduction of primitive hematopoietic stem cells.38

Retinoic acid receptors and myelopoiesis – in vivo models

The above studies assessing the effect of ATRA on cultured hematopoietic cells in vitro have generated complex and occasionally contrasting results likely secondary to the large number of experimental variables inherent in such approaches. Such variables include the degree of maturity of the starting target cell population, the cytokines present in the culture media and whether the cultures are performed in liquid suspension or in semi-solid media. Moreover, most of these studies have involved utilizing relatively high ‘pharmacological’ concentrations of retinoic acid (0.1–1 μM) which is 100–1000-fold higher than the endogenous ‘physiological’ concentration of retinoids (1–10 nM) normally present in serum.39,40 Thus the contribution of normal circulating levels of retinoids to hematopoiesis remains unclear. Some of these problems can be overcome utilizing a number of in vivo models of retinoid and retinoic acid receptor function including vitamin A deficient (VAD) mice, mice treated with synthetic RAR antagonists,26,27 and knock-out mice genetically deficient in one or more of the retinoic acid receptors.

Vitamin A-deficient mice

Retinoic acid is a derivative of vitamin A (retinol) and several models of vitamin A-deficient (VAD) mice have been utilized to determine the role that endogenous retinoids might play in hematopoiesis. Mice of the SENCAR strain when fed a vitamin A-deficient diet develop within 3–5 weeks a severe retinol deficiency that has been previously associated with abnormalities in skin and cervical epithelium.41,42 Such VAD mice develop an expansion of myeloid cells in the bone marrow, spleen and peripheral blood.43 These myeloid cells were predominantly granulocytes expressing the Mac-1 and Gr-1 surface antigen profile characteristic of mature, terminally differentiating granulocytes, and no block to their differentiation was noted in these VAD mice. Moreover, in vitro colony-forming assays revealed no significant difference in the number of myeloid progenitors between the VAD vs the control mice, and these mice did not show any obvious abnormalities in their numbers of B and T lymphocytes.43 Importantly, when the diet was again supplemented with ATRA, the myeloid expansion reverted back to normal. The authors suggest that the myeloid expansion in the VAD mice might be related to the reduced spontaneous apoptosis of granulocytes observed in these animals.43 Indeed retinoids have been previously observed to regulate apoptosis of cultured myeloid cells.44,45

A similar myeloid expansion was also observed in cellular retinol-binding protein type I (CRBPI)-deficient mice. CRBPI homozygous knock-out mice harbor low vitamin A stores and develop severe vitamin A deficiency when fed a vitamin A deficient diet.46 These animals also display an expansion of neutrophils in the spleen and blood, but in contrast with the observations in the VAD SENCAR mice, the CRBPI−/− mice depleted of vitamin A exhibit an increase in the proportion of relatively immature Mac-1low/+GR-1−/low granulocytes that accompany this myeloid expansion.47 A similar myeloid expansion associated with an increase in immature granulocytes was also observed in wild-type mice treated with the pan-RAR antagonist BMS493.47 This expansion of the myeloid compartment with enhanced expression of immature granulocytes observed in the CRBPI−/− mice, as well as in mice treated with RAR antagonists indicates that endogenous retinoids play a role in encouraging the terminal differentiation/apoptosis of myeloid cells, an activity that clearly mimics their role in inducing the terminal differentiation of malignant promyelocytes.9,10,11,12

RA receptor knock-out mice

In the above vitamin A-deficient mouse models the ligand-mediated activity of all the retinoic acid receptors including the RARs (RARα, β and λ), as well as the RXRs (RXRα, β and λ) is presumably inhibited. The effect on hematopoiesis of selectively disrupting individual RA receptors has been explored in knock-out mice. RARβ is generally poorly expressed in myeloid cells while both RARα and RARγ expression is readily detected,48 and thus the knock-out studies assessing hematopoiesis have concentrated on these latter two RARs. Two isoforms of RARα (RARα1 and RARα2) harbor divergent AF-1 domains and are expressed in many different tissues including hematopoietic cells.49 Mice selectively deficient in the RARα1 isoform appear normal with no discernible disorder in hematopoiesis.48,50 In contrast knockout mice in which both isoforms of RARα have been disrupted display early post natal lethality and testis degeneration, but do not display any overt abnormality in hematopoiesis.51 Similarly, RARγ homozygous knock-out mice do not display any abnormality in myelopoiesis.52 RARα−/−RARγ−/− double mutants die in utero,53 and thus examination of hematopoiesis in these animals has been largely confined to the fetal liver. Fetal liver cells from the RARα−/−RARγ−−/− double mutant animals consist of mostly mature granulocytes that display similar morphology, surface antigen phenotype (Mac-1,GR-1) and gene expression pattern as wild-type mice.47 Moreover, these animals do not display any enhanced RARβ expression that might compensate for the RARα and RARγ deficiency. Interestingly, both liquid suspension and methylcellulose cultures of bone marrow cells from RARα−/− mice displayed an increase and/or acceleration of granulocytic differentiation suggesting that RARα, in the absence of ligand might normally be involved in suppressing granulopoiesis.47,54

The normal granulopoiesis observed in the fetal livers of the RARα−/−RARγ−/− double mutant animals in the absence of RARβ expression strongly indicates that the RARs are not essential and are in fact dispensible for granulopoiesis. Thus these studies on knock-out mice together with the studies in the VAD animals clearly indicate that granulopoiesis can occur in the absence of RAR activity, and retinoids and RARs are likely involved in modifying granulopoiesis but are not essential regulators.47

Target genes for the RA receptors in hematopoietic cells

The retinoic acid receptors are transcription factors which bind as RAR-RXR heterodimers to particular sequences, the retinoic acid response elements (RAREs) in the regulatory region of specific target genes (Figure 1). These RAREs generally consist of a direct repeat (5′ PuGTTCA-3′) separated by either 2 (DR2) or 5 (DR5) base pairs.3,55 What are the target genes for the RA receptors that are likely involved in the RA receptor regulation of both normal and malignant myelopoiesis? A variety of different potential RAR target genes have been identified in different model systems. Indeed studies utilizing expression microarrays have identified extensive changes in gene expression that accompany the retinoic acid-induced differentiation of a number of myeloid cell lines.56,57 Here we discuss a number of individual genes regulated by retinoic acid that appear to have particular relevance to both normal and malignant myelopoiesis.

Figure 1
figure1

The RXR-RAR heterodimers. RA receptors harbor distinct ligand binding (LBD) and DNA binding domains (DBD). The RXR-RAR heterodimer binds to specific gene promoter target sequences, the retinoic acid response elements (RAREs). Here is illustrated a DR5 RARE with a 6 bp direct repeat separated by a 5 bp ‘spacer’ element.

c-myc

HL-60 cells were derived from a patient initially diagnosed with acute promyelocytic leukemia58,59 although a subsequent morphologic assessment indicated that the primary leukemia cells were more appropriately classified as an FAB-M2 leukemia (AML with maturation) rather than FAB-M3.60 HL-60 cells exhibit a 15–30-fold amplification of the c-myc cellular oncogene compared with normal cells.61 Retinoic acid induces the terminal granulocytic differentiation of these cells,62 and this differentiation is mediated directly through the retinoic acid receptor.63 This retinoic acid-induced differentiation of HL-60, as well as other myeloid cell lines, is invariably accompanied by the down-regulation of c-myc mRNA expression.64,65,66 Moreover, a similar decrease in c-myc expression has been observed during the differentiation of normal myeloid progenitors.67 C-myc is a transcription factor involved in regulating proliferation and apoptosis, and enhanced c-myc expression is commonly observed in human malignancies.68,69 Thus the molecular basis for the RAR-mediated down-regulation of c-myc expression has been of considerable interest. Nevertheless no RAREs have been identified in the c-myc gene promoter suggesting that activated RA receptors do not directly bind to the c-myc locus. However, a deletion analysis of the c-myc promoter transfected into HL-60 cells induced with retinoic acid identified a retinoic acid responsive element within the P2 promoter of the c-myc gene. This element harbors an E2F site70 which appears to be a critical regulator of c-myc transcription.71,72 Interestingly C/EBPα, another critical regulator of granulopoiesis73,74,75 also down-regulates c-myc expression through this same E2F site.76 How these different transcription factors might interact with E2F or other molecules to down-regulate c-myc expression at this site is presently unclear.

Stra-13

Stra-13 is a basic helix–loop–helix protein that was originally identified as a gene that was rapidly induced by retinoic acid in P19 embryonal carcinoma cells.77 Stra-13 expression is associated with growth arrest, as well as diminished c-myc expression,78 and Stra-13−/− mice display lymphoid hyperproliferation with an associated spontaneous activation of T and B cells leading to autoimmune disease.79 In transient transfection assays Stra-13 down-regulates the c-myc promoter,78 and thus this retinoic acid-inducible gene may be involved in the down-regulation of c-myc expression that accompanies myeloid differentiation. Although this gene is clearly RA inducible, to date a RARE has not been identified in the Stra-13 promoter (R Taneja, personal communication), and thus whether this gene is directly or indirectly regulated by RA receptors is presently unclear.

C/EBPε

C/EBPε is member of the CCAAT/enhancer binding protein family of transcription factors80 and is preferentially expressed in terminally differentiating granulocytes.81,82,83 C/EBPε−/− mice display neutrophil dysfunction leading to opportunistic infections and myelodysplasia,84 and inactivating mutations of C/EBPε have been observed in individuals with congenital neutrophil-specific granule deficiency.85,86 Moreover, in certain cell lines G-CSF likely enhances granulocytic differentiation by directly up-regulating C/EBPε expression.87 Thus C/EBPε appears to be a critical regulator of granulopoiesis. The retinoic acid-induced granulocytic differentiation of promyelocytic leukemia cell lines is associated with enhanced C/EBPε mRNA expression, and a RARE (DR5) has been identified in the C/EBPε promoter.88 Thus C/EBPε appears to be a direct target of the activated RA receptors. The role played by other hematopoietic transcription factors in regulating C/EBPε expression is presently unclear, and it would be of interest to determine relative expression levels of C/EBPε in the granulocytes of the RARα−/− and RARα−/−RARγ−/− mutant mice.47 It would also be of interest to determine whether RA receptors can influence granulocytic differentiation in the absence of C/EBPε. Previous studies suggest that RA-induced granulocytic differentiation might ‘bypass’ other important regulators of myelopoiesis. For example although C/EBPα is a critical in vivo regulator of granulopoiesis,73,74,75 nevertheless cytokine-dependent cell lines derived from C/EBPα−/− mice display brisk retinoic acid-induced granulocytic differentiation.89

Hox family members

The Hox genes harbor a highly conserved 183 nucleotide DNA-binding homeodomain related to Drosophila Antennapedia. The class I Hox genes are arranged in four clusters (A to D) of 9–11 genes/cluster localized on four different chromosomes, and their regulated expression is critical to establishing segment identity during embryogenesis.90 During hematopoietic development the class I Hox family members, particularly the Hox A and Hox B clusters also display differential expression, with those at the 3′ end generally expressed in relatively immature cells, while those at the 5′ end expressed later in hematopoietic development.91,92 There is considerable evidence that certain Hox genes are important regulators of hematopoiesis. When overexpressed in hematopoietic cells certain of these genes including HoxB493 HoxB794 and HoxA1095 will block differentiation and/or expand progenitor cell numbers both in vitro and in vivo. Moreover, chromosome translocations involving the HoxA9 gene have been observed in human myelogenous leukemia96,97 and retroviral insertional activations of both the Hoxa-9 and Hoxa-7 genes have been identified in the BXH-2 mouse model of myeloid leukemia.98 These observations indicate that the Hox genes might normally play an important role in regulating the proliferation/differentiation of hematopoietic cells. Retinoic acid has been implicated in regulating Hox gene expression during embryogenesis,99 and in embryonal carcinoma cell lines there is differential sensitivity of the Hox family members to ATRA with those at the 3′ end of the cluster more readily activated than those at the 5′ end of the cluster.100 Indeed a number of Hox genes harbor well-defined RAREs in their promoters.101,102,103,104 Despite these intriguing potential associations between Hox gene expression, RA receptor activity and the regulation of hematopoietic cell growth and differentiation, there is no clear evidence that the retinoids or the RA receptors are involved in regulating the expression/activity of any Hox family members during hematopoiesis.

p21

The p21WAF1/CIP1 gene interacts with and inhibits various cyclin-dependent kinase (CDK) complexes that are involved in regulating cell cycle progression.105 Differentiation is frequently accompanied by exit from the cell cycle, and p21 is frequently up-regulated during the terminal differentiation of a number of different cell types. The retinoic acid-induced granulocytic differentiation of HL-60 cells, as well as the RA-induced monocytic differentiation of U937 cells is associated with enhanced p21 expression.106,107,108 The activities of p21 are complex, and at low concentrations this protein enhances active CDK complex formation while at higher concentrations it inhibits CDK activity.109,110 P21 mRNA expression is enhanced in myeloid colonies derived from CD34+ cells,111 and p21 levels progressively rise during cytokine-induced differentiation of CD34+ cells before falling during terminal differentiation.112 The p21 promoter harbors an RARE (DR5) suggesting that it is directly regulated by activated RA receptors.108 Together these observations suggest that p21 may be a critical target gene for RA receptors during granulopoiesis. However, enhanced p21 expression does not appear to be absolutely necessary for regulating terminal granulocytic differentiation since p21−/− mice do not have any observed defect in myelopoiesis.113,114

RARα2 isoform

There are two isoforms of RARα (RARα1 and RARα2) which completely diverge in their N-terminal AF-1 domain as a result of alternative promoter/exon usage and alternative splicing (Figure 2a, b). Interestingly, the promoter generating the mRNA for the A2 isoform (designated P2) harbors an RARE while the promoter generating the A1 isoform (designated P1) does not.49,115,116 This promoter structure is evolutionarily conserved as the RARβ2 isoform also harbors an RARE that is not present in the RARβ1 isoform.117,118,119 Expression of mRNA for the RARα2 isoform is increased during the myeloid differentiation of FDCP mix A4 cells and also accompanies the retinoic acid induced differentiation of NB-4 and HL-60 cells.25 Moreover, during retinoid-induced differentiation of the GM-CSF-dependent MPRO cells, which provides a robust in vitro model for granulocytic differentiation,13,57 we have observed enhanced expression of the RARα2 vs the RARα1 isoform (Figure 2c). Together these observations suggest that the RARα2 isoform might be a direct target for the activated RA receptor during granulocytic differentiation and that this triggers an autoregulatory positive feedback loop with the RARα2 isoform enhancing its own expression. It is possible that the RARα2 isoform displays enhanced functional activity compared with the RARα1 isoform in differentiating myeloid cells, but this has not been experimentally confirmed.

Figure 2
figure2

Structure and expression of the RARα gene. (a) The RARα genomic locus. The P2 promoter harbors a retinoic acid response element (RARE) while the P1 promoter does not. (b) Specific RARα isoforms (A1 vs A2) harboring distinct AF-1 domains are generated by alternative promoter usage (P1 vs P2). (c) RT-PCR analysis of MPRO cells serially harvested following differentiation induction with ATRA. Primers specific for the RARα A1 vs the RARα A2 isoforms were utilized as indicated.

Non-ligand-mediated regulation of RA receptor activity in hematopoietic cells

The above studies indicate that RA receptors are important regulators of myelopoiesis, and that they likely exert their activity by acting as transcription factors to regulate the expression of specific target genes. The RARs were originally identified as members of the nuclear hormone receptor family of transcription factors whose activity was regulated by the addition of exogenous retinoic acid.120,121 But if ligand concentration alone is the critical factor in regulating RA receptor activity, then how is RA receptor transcriptional activity differentially regulated in hematopoietic cells that presumably are exposed to the uniform ‘physiologic’ concentrations of retinoids that are present in serum (1–10 nM)? One possibility is that different hematopoietic cells metabolize retinoic acid precursors such as retinol (vitamin A) or retinaldehyde at different rates resulting in differences in the intracellular concentration of specific retinoids in different cell types. For example aldehyde dehydrogenase (ALDH), an enzyme that oxidizes retinal to retinoic acid122 is preferentially expressed in early hematopoietic stem cells.123,124 However the physiological/biological consequences of this enhanced ALDH expression with respect to stem cell activity is presently unclear. Alternatively, RA receptor activity might be subject to non-ligand-mediated mechanisms of regulation that might be active in cells at different stages of myeloid differentiation. For example, in the relatively immature, multipotent, SCF-dependent EML cells,28 the transcriptional activity of the RA receptors in response to ligand is relatively blunted, but in the more mature GM-CSF-dependent MPRO promyelocytes13 there is a marked increase in both ligand-dependent and ligand-independent activity of the RA receptors.29 These observations suggest that RA receptor activity might be developmentally regulated during different stages of myelopoiesis. The histone deacetylase inhibitor, trichostatin A (TSA), readily activates a retinoic acid responsive reporter in the immature EML cells, but not in the more mature MPRO cells suggesting that there are functionally significant differences in repressor complexes harboring HDAC activity in these different hematopoietic lineages.29,30 Interestingly TSA also frequently activates reporters driven by RAREs in primary myeloid leukemia samples indicating that repression of RA receptor transcriptional activity may commonly occur in human AML.125 However, the molecular basis for this inhibition of RA receptor transcriptional activity in primary AML cells is presently unknown.

Cytokines and RA receptor activity

Hematopoietic cytokines, particularly IL-3, GM-CSF and IL-1 have been observed to enhance the ATRA-mediated differentiation of primary human APL cells.126 Moreover, such cytokines appear to be important mediators of RA receptor transcriptional activity, since the addition of IL-3 or GM-CSF to the SCF-dependent EML cells, as well as to normal cultured hematopoietic precursors is associated with enhanced transcriptional activity of the RA receptors.30 Many cytokines, such as IL-3 and GM-CSF, mediate their biological activities by activating the Jak/Stat pathway. Stats are recruited to activated cytokine receptors where they undergo phosphorylation mediated by their associated JAKs. The activated Stats then translocate to the nucleus where they serve as transcription factors to activate specific target genes.127,128 Stat family members generally display binding to the consensus sequence ‘TTC(N)2–4GAA’ present in the promoters of their target genes.129 Recent observations suggest that there may be significant functional cross-talk between the Stat and RA receptor families of transcription factors. For example, the IL-3-mediated enhancement of RA receptor activity observed in EML cells30 is directly mediated through Stat5.130 Moreover, there are overlapping Stat/RAR binding sites in the retinoic acid responsive elements (RAREs) of a number of different genes, and Stat5 and RA receptors associate in vivo in a cytokine-dependent manner.130 The nature of the molecular interaction between Stat and RA receptor family members, as well as their functional consequences are presently unclear. However, such physical and functional interactions between Stats and RA receptors may account for some of the non-ligand-mediated regulation of RA receptor activity that appears to occur at different stages of myelopoiesis.

Protein kinase A (PKA) and RA receptor activity

A number of studies have suggested close synergy between PKA and RA receptor activation in triggering the differentiation of myeloid leukemia cells. The retinoic acid-induced differentiation of the HL-60 and U-937 cell lines is markedly potentiated by the addition of agents that increase intracellular cAMP, which is a direct activator of PKA.131,132 Certain NB-4 subclones that are resistant to ATRA alone exhibit enhanced differentiation when exposed to ATRA plus cAMP analogs.133 Moreover, certain RXR agonists which are inactive by themselves in inducing NB4 cell differentiation can activate differentiation in combination with the PKA agonist 8CPT-cAMP.134 PKA phosphorylates RARα at specific amino acids within the dimerization domain of RARα, and this appears to enhance RA receptor activity in CV-1 cells.135 PKA also phosphorylates certain of the RAR transcriptional coactivators and enhances their activity,136 and this might also explain the synergistic activity of PKA and RAR agonists in triggering the differentiation of certain leukemia cells.

Disruption of RARα activity and the development of promyelocytic leukemia

Human acute promyelocytic leukemia (APL) is associated with different chromosome translocations involving RARα. At least five different fusion partners for RARα have been described with the great majority involving either the PML or PLZF genes.137,138 There is considerable biochemical evidence suggesting that these aberrant fusion proteins function in a dominant negative manner to disrupt the transcriptional activity of the wild-type RARα gene. In the absence of ligand normal RARα transcriptional activity is likely inhibited by its interaction with certain corepressors, particularly N-CoR/SMRT, and the addition of ATRA results in the release of such corepressors and recruitment of transcriptional coactivators.139 The leukemia-specific fusion proteins, including PML-RARα, display a higher avidity for such corepressors, and significantly higher concentrations of ATRA are required to dissociate the corepressors from PML-RARα compared with the wild-type RARα.6,7,140,141 Interestingly, in contrast with PML-RARα, the leukemias associated with PLZF-RARα are generally insensitive to retinoic acid,142,143 and PLZF-RARα binding to corepressors is also insensitive to high concentrations of ATRA.6,7,140,141

Although the above studies suggest that the RARα fusion proteins characterizing APL act in a dominant negative manner to disrupt normal RARα activity, this likely does not entirely account for the leukemogenic activity of these aberrant proteins. Indeed as noted above, the RA receptor knock-out mouse studies indicate that RA receptors are not absolutely required for normal granulopoiesis, raising the question of how blocking RA receptor activity might lead to the block in granulocytic differentiation that characterizes APL. Moreover, while transduction of dominant negative RARs into normal mouse bone marrow leads to the development of cell lines frozen at different stages of myeloid differentiation,13,28 nevertheless these cell lines are not leukemogenic when injected into syngeneic animals (unpublished). Thus more than just disruption of RARα activity may be necessary for overt leukemia to occur. Indeed in PML-RARα leukemias, transformation may result from interference with the activity of both PML and RARα. PML is a growth suppressor with proapoptotic function,144,145,146 and this anti-proliferative activity of PML may be related to its functional interaction with p53.147 The PML-RARα fusion protein may interfere with this pro-apoptotic activity of PML, and this may be a critical event in the pathogenesis of APL.148 Similarly in certain myeloid cell lines PLZF enhances growth suppression, and PLZF-RARα-mediated disruption of this activity combined with its dominant negative effect on normal RARα may contribute to the leukemic phenotype.149

Summary

Studies with knock-out mice indicate that the retinoic acid receptors are non-essential and indeed appear to be dispensible for normal hematopoiesis. However both in vitro and in vivo studies indicate that all-trans retinoic acid (ATRA) and the retinoic acid receptors play an important role in modifying/regulating hematopoiesis and may also directly or indirectly enhance the ex vivo maintenance/viability of transplantable hematopoietic stem cells. A growing number of target genes have been identified that are directly or indirectly regulated by the activated RA receptors and that are likely directly involved in this regulation of hematopoiesis. Non-ligand-mediated regulation of RA receptor activity appears to characterize different stages of myelopoiesis, and this may involve the interaction of RA receptors with transcriptional corepressors or with other transcription factors such as the Stat family members. This non-ligand-mediated regulation of RA receptor activity may have relevance to the differential sensitivity of human myelogenous leukemia cells to retinoic acid. Paradoxically it is the myeloid leukemia cells that harbor dominant negative retinoic acid receptors (eg PML-RARα) that exhibit a therapeutic response to ATRA, while the other types of human myeloid leukemia cells, which generally harbor normal RA receptors,150 display virtually no response to this agent. Since the malignant phenotype often reflects the underlying phenotype of the normal cells from which the transformed cells arise, defining the molecular basis for the differential activation of RA receptors in normal hematopoietic development may have direct relevance to the question of why some human myeloid leukemias (ie APL) respond dramatically to retinoids while most others (the non-APL leukemias) do not.

References

  1. 1

    Alcalay M, Zangrilli D, Pandolfi P, Longo L, Mencarelli A, Giacomucci A, Rocchi M, Biondi A, Rambaldi A, LoCoco F, Diverioi D, Donti E, Grignani F, Pelicci P . Translocation breakpoint of acute promyelocytic leukemia lies within the retinoic acid receptor alpha locus Proc Natl Acad Sci USA 1991 88: 1977–1981

    CAS  PubMed  Google Scholar 

  2. 2

    de Thé H, Marchio A, Chomienne C, Degos L, Dejean A . The PML-RARalpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR Cell 1991 66: 675–684

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    Kakizuka A, Miller W, Umesono K, Warrell R, Frankel S, Murty V, Dmitrovsky E, Evans R . Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML Cell 1991 66: 663–674

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Kastner P, Perez A, Lutz Y, Rochette-Egly C, Gaub MP, Durand B, Lanotte M, Berger R, Chambon P . Structure, localization and transcriptional properties of two classes of retinoic acid receptor alpha fusion proteins in acute promyelocytic leukemia (APL): structural similarities with a new family of oncoproteins Embo J 1992 11: 629–642

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Pandolfi PP, Alcalay M, Longo L, Fagioli M, Zangrilli D, Grignani F, Menccarelli A, Biondi A, Rambaldi A, LoCoco F, Grigani F, Pelicci PG . Molecular genetics of the t(15;17) of acute promyelocytic leukemia (APPL) Leukemia 1992 6 (Suppl 3): 120S–122S

    Google Scholar 

  6. 6

    Lin R, Nagy L, Inoue S, Shao W, Miller W, Evans R . Role of the histone deacetylase complex in acute promyelocytic leukemia Nature 1998 391: 811–814

    CAS  Google Scholar 

  7. 7

    He L-Z, Guidez F, Tribioli C, Peruzzi D, Ruthardt M, Zelent A, Pandolfi PP . Distinct interactions of PML-RARa and PLZF-RARa with co-repressors determine differential responses to RA in APL Nature Genet 1998 18: 126–135

    CAS  PubMed  Google Scholar 

  8. 8

    Pandolfi PP . Oncogenes and tumor suppressors in the molecular pathogenesis of acute promyelocytic leukemia Hum Mol Genet 2001 10: 769–775

    CAS  PubMed  Google Scholar 

  9. 9

    Huang M, 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 1988 72: 567–574

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Castaigne S, Chomienne C, Daniel M, Berger N, Fenaux P, Degos L . All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results Blood 1990 76: 1704–1712

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Warrell R, Frankel S, Miller W, Itri L, Andreef M, Jabukowski A, Gabrilove J, Gordon M, Dmitrovsky E . Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans retinoic acid) New Engl J Med 1991 324: 1385–1390

    Google Scholar 

  12. 12

    Tallman M, Andersen J, Schiffer C, Appelbaum F, Feusner J, Ogden A, Shepard L, Willman C, Bloomfield C, Rowe J, Wiernik P . All-trans retinoic acid in acute promyelocytic leukemia New Engl J Med 1997 337: 1021–1028

    CAS  Google Scholar 

  13. 13

    Tsai S, Collins S . A dominant negative retinoic acid receptor blocks neutrophil differentiation at the promyelocyte stage Proc Natl Acad Sci USA 1993 90: 7153–7157

    CAS  Google Scholar 

  14. 14

    Douer D, Koeffler H . Retinoic acid enhances colony-stimulating factor-induced clonal growth of normal human myeloid progenitor cells in vitro Exp Cell Res 1982 138: 193–198

    CAS  Google Scholar 

  15. 15

    Nagler A, Riklis I, Kletter Y, Tatarsky I, Fabian I . Effect of 1,25 dihydroxyvitamin D3 and retinoic acid on normal human pluripotent (CFU-mix), erythroid (BFU-E), and myeloid (CFU-C) progenitor cell growth and differentiation patterns Exp Hematol 1986 14: 60–65

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Tobler A, Dawson MI, Koeffler HP . Retinoids. Structure-function relationship in normal and leukemic hematopoiesis in vitro J Clin Invest 1986 78: 303–309

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Sakashita A, Kizaki M, Pakkala S, Schiller G, Tsuruoka N, Tomosaki R, Cameron JF, Dawson MI, Koeffler HP . 9-cis-retinoic acid: effects on normal and leukemic hematopoiesis in vitro Blood 1993 81: 1009–1016

    CAS  PubMed  Google Scholar 

  18. 18

    Gratas C, Menot ML, Dresch C, Chomienne C . Retinoid acid supports granulocytic but not erythroid differentiation of myeloid progenitors in normal bone marrow cells Leukemia 1993 7: 1156–1162

    CAS  Google Scholar 

  19. 19

    Labbaye C, Valtieri M, Testa U, Giampaolo A, Meccia E, Sterpetti P, Parolini I, Pelosi E, Bulgarini D, Cayre YE . Retinoic acid downmodulates erythroid differentiation and GATA1 expression in purified adult-progenitor culture Blood 1994 83: 651–656

    CAS  Google Scholar 

  20. 20

    Rusten LS, Dybedal I, Blomhoff HK, Blomhoff R, Smeland EB, Jacobsen SE . The RAR-RXR as well as the RXR-RXR pathway is involved in signaling growth inhibition of human CD34+ erythroid progenitor cells Blood 1996 87: 1728–1736

    CAS  PubMed  Google Scholar 

  21. 21

    Tocci A, Parolini I, Gabbianelli M, Testa U, Luchetti L, Samoggia P, Masella B, Russo G, Valtieri M, Peschle C . Dual action of retinoic acid on human embryonic/fetal hematopoiesis: blockade of primitive progenitor proliferation and shift from multipotent/erythroid/monocytic to granulocytic differentiation program Blood 1996 88: 2878–2888

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Zauli G, Visani G, Vitale M, Gibellini D, Bertolaso L, Capitani S . All-trans retinoic acid shows multiple effects on the survival, proliferation and differentiation of human fetal CD34+ haemopoietic progenitor cells Br J Haematol 1995 90: 274–282

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Spooncer E, Heyworth CM, Dunn A, Dexter TM . Self-renewal and differentiation of interleukin-3-dependent multipotent stem cells are modulated by stromal cells and serum factors Differentiation 1986 31: 111–118

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Heyworth CM, Dexter TM, Kan O, Whetton AD . The role of hemopoietic growth factors in self-renewal and differentiation of IL-3-dependent multipotential stem cells Growth Factors 1990 2: 197–211

    CAS  PubMed  Google Scholar 

  25. 25

    Zhu J, Heyworth CM, Glasow A, Huang QH, Petrie K, Lanotte M, Benoit G, Gallagher R, Waxman S, Enver T, Zelent A . Lineage restriction of the RARalpha gene expression in myeloid differentiation Blood 2001 98: 2563–2567

    CAS  Google Scholar 

  26. 26

    Apfel C, Bauer F, Crettaz M, Forni L, Kamber M, Kaufmann F, LeMotte P, Pirson W, Klaus M . A retinoic acid receptor alpha antagonist selectively counteracts retinoic acid effects Proc Natl Acad Sci USA 1992 89: 7129–7133

    CAS  Google Scholar 

  27. 27

    Johnson A, Klein E, Gillet S, Wang L, Song T, Pino M, Chandraratna RAS . Synthesis and characterization of a highly potent and effective antagonist of retinoic acid receptors J Med Chem 1995 38: 4764–4767

    CAS  PubMed  Google Scholar 

  28. 28

    Tsai S, Bartelmez S, Sitnicka E, Collins S . Lymphohematopoietic progenitors immortalized by a retroviral vector harboring a dominant negative retinoic acid receptor can recapitulate lymphoid, myeloid and erythroid development Genes Dev 1994 8: 2831–2842

    CAS  PubMed  Google Scholar 

  29. 29

    Johnson B, Chandraratna R, Heyman R, Allegretto E, Mueller L, Collins S . RXR agonist-induced activation of dominant negative RXR-RAR*403 heterodimers is developmentally regulated during myeloid differentiation Mol Cell Biol 1999 19: 3372–3382

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Johnson BS, Mueller L, Si J, Collins SJ . The cytokines IL-3 and GM-CSF regulate the transcriptional activity of retinoic acid receptors in different in vitro models of myeloid differentiation Blood 2002 99: 746–753

    CAS  PubMed  Google Scholar 

  31. 31

    Smeland EB, Rusten L, Jacobsen SE, Skrede B, Blomhoff R, Wang MY, Funderud S, Kvalheim G, Blomhoff HK . All-trans retinoic acid directly inhibits granulocyte colony-stimulating factor-induced proliferation of CD34+ human hematopoietic progenitor cells Blood 1994 84: 2940–2945

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Tohda S, Minden MD, McCulloch EA . Interactions between retinoic acid and colony-stimulating factors affecting the blast cells of acute myeloblastic leukemia Leukemia 1991 5: 951–957

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Douer D, Ramezani L, Parker J, Levine AM . All-trans retinoic acid effects the growth, differentiation and apoptosis of normal human myeloid progenitors derived from purified CD34+ bone marrow cells Leukemia 2000 14: 874–881

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Purton L, Bernstein I, Collins S . All-trans retinoic acid enhances the long-term repopulating activity of cultured hematopoietic stem cells Blood 2000 95: 470–477

    CAS  PubMed  Google Scholar 

  35. 35

    Lardon F, Snoeck HW, Haenen L, Lenjou M, Nijs G, Weekx SF, Van Ranst PC, Berneman ZN, Van Bockstaele DR . The combined effects of all-trans retinoic acid and TGF-beta on the initial proliferation of normal human bone marrow progenitor cells Leukemia 1996 10: 1937–1943

    CAS  PubMed  Google Scholar 

  36. 36

    Jacobsen SE, Fahlman C, Blomhoff HK, Okkenhaug C, Rusten LS, Smeland EB . All-trans- and 9-cis-retinoic acid: potent direct inhibitors of primitive murine hematopoietic progenitors in vitro J Exp Med 1994 179: 1665–1670

    CAS  PubMed  Google Scholar 

  37. 37

    Purton LE, Dworkin S, Fero J, Simmons PJ, Collins SJ . Treatment of primary Lin-c-kit+Sca-1+ cells with all-trans retinoic acid dramatically increases their serial transplant potential Blood 2001 98: 453a

    Google Scholar 

  38. 38

    Purton LE, Morris JC, Bernstein ID, Collins SJ, Kiem HP . All-trans retinoic acid facilitates oncoretrovirus-mediated transduction of hematopoietic repopulating stem cells J Hematother Stem Cell Res 2001 10: 815–825

    CAS  PubMed  Google Scholar 

  39. 39

    De Ruyter MG, Lambert WE, De Leenheer AP . Retinoic acid: an endogenous compound of human blood. Unequivocal demonstration of endogenous retinoic acid in normal physiological conditions Anal Biochem 1979 98: 402–409

    CAS  PubMed  Google Scholar 

  40. 40

    Muindi JR, Frankel SR, Huselton C, DeGrazia F, Garland WA, Young CW, Warrell RP Jr . Clinical pharmacology of oral all-trans retinoic acid in patients with acute promyelocytic leukemia Cancer Res 1992 52: 2138–2142

    CAS  PubMed  Google Scholar 

  41. 41

    Darwiche N, Celli G, Sly L, Lancillotti F, De Luca LM . Retinoid status controls the appearance of reserve cells and keratin expression in mouse cervical epithelium Cancer Res 1993 53 (10 Suppl): 2287–2299

    Google Scholar 

  42. 42

    De Luca LM, Shores RL, Spangler EF, Wenk ML . Inhibition of initiator-promoter-induced skin tumorigenesis in female SENCAR mice fed a vitamin A-deficient diet and reappearance of tumors in mice fed a diet adequate in retinoid or beta-carotene Cancer Res 1989 49: 5400–5406

    CAS  PubMed  Google Scholar 

  43. 43

    Kuwata T, Wang IM, Tamura T, Ponnamperuma RM, Levine R, Holmes KL, Morse HC, De Luca LM, Ozato K . Vitamin A deficiency in mice causes a systemic expansion of myeloid cells Blood 2000 95: 3349–3356

    CAS  PubMed  Google Scholar 

  44. 44

    Nagy L, Thomazy VA, Shipley GL, Fesus L, Lamph W, Heyman RA, Chandraratna RA, Davies PJ . Activation of retinoid X receptors induces apoptosis in HL-60 cell lines Mol Cell Biol 1995 15: 3540–3551

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Mehta K, McQueen T, Neamati N, Collins S, Andreeff M . Activation of retinoid receptors RAR alpha and RXR alpha induces differentiation and apoptosis, respectively, in HL-60 cells Cell Growth Differ 1996 7: 179–186

    CAS  PubMed  Google Scholar 

  46. 46

    Ghyselinck NB, Bavik C, Sapin V, Mark M, Bonnier D, Hindelang C, Dierich A, Nilsson CB, Hakansson H, Sauvant P, Azais-Braesco V, Frasson M, Picaud S, Chambon P . Cellular retinol-binding protein I is essential for vitamin A homeostasis Embo J 1999 18: 4903–4914

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Kastner P, Lawrence HJ, Waltzinger C, Ghyselinck NB, Chambon P, Chan S . Positive and negative regulation of granulopoiesis by endogenous RARalpha Blood 2001 97: 1314–1320

    CAS  PubMed  Google Scholar 

  48. 48

    Labrecque J, Allan D, Chambon P, Iscove NN, Lohnes D, Hoang T . Impaired granulocytic differentiation in vitro in hematopoietic cells lacking retinoic acid receptors alpha1 and gamma Blood 1998 92: 607–615

    CAS  Google Scholar 

  49. 49

    Leroy P, Krust A, Zelent A, Mendelsohn C, Garnier JM, Kastner P, Dierich A, Chambon P . Multiple isoforms of the mouse retinoic acid receptor alpha are generated by alternative splicing and differential induction by retinoic acid Embo J 1991 10: 59–69

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Li E, Sucov HM, Lee KF, Evans RM, Jaenisch R . Normal development and growth of mice carrying a targeted disruption of the alpha 1 retinoic acid receptor gene Proc Natl Acad Sci USA 1993 90: 1590–1594

    CAS  PubMed  Google Scholar 

  51. 51

    Lufkin T, Lohnes D, Mark M, Dierich A, Gorry P, Gaub MP, LeMeur M, Chambon P . High postnatal lethality and testis degeneration in retinoic acid receptor alpha mutant mice Proc Natl Acad Sci USA 1993 90: 7225–7229

    CAS  PubMed  Google Scholar 

  52. 52

    Lohnes D, Kastner P, Dierich A, Mark M, LeMeur M, Chambon P . Function of retinoic acid receptor gamma in the mouse Cell 1993 73: 643–658

    CAS  Google Scholar 

  53. 53

    Lohnes D, Mark M, Mendelsohn C, Dolle P, Dierich A, Gorry P, Gansmuller A, Chambon P . Function of the retinoic acid receptors (RARs) during development (I). Craniofacial and skeletal abnormalities in RAR double mutants Development 1994 120: 2723–2748

    CAS  PubMed  Google Scholar 

  54. 54

    Du C, Redner RL, Cooke MP, Lavau C . Overexpression of wild-type retinoic acid receptor alpha (RARalpha) recapitulates retinoic acid-sensitive transformation of primary myeloid progenitors by acute promyelocytic leukemia RARalpha-fusion genes Blood 1999 94: 793–802

    CAS  PubMed  Google Scholar 

  55. 55

    Glass CK . Differential recognition of target genes by nuclear receptor monomers, dimers, and heterodimers Endocr Rev 1994 15: 391–407

    CAS  PubMed  Google Scholar 

  56. 56

    Liu TX, Zhang JW, Tao J, Zhang RB, Zhang QH, Zhao CJ, Tong JH, Lanotte M, Waxman S, Chen SJ, Mao M, Hu GX, Zhu L, Chen Z . Gene expression networks underlying retinoic acid-induced differentiation of acute promyelocytic leukemia cells Blood 2000 96: 1496–1504

    CAS  Google Scholar 

  57. 57

    Lian Z, Wang L, Yamaga S, Bonds W, Beazer-Barclay Y, Kluger Y, Gerstein M, Newburger PE, Berliner N, Weissman SM . Genomic and proteomic analysis of the myeloid differentiation program Blood 2001 98: 513–524

    CAS  Google Scholar 

  58. 58

    Collins S, Gallo R, Gallagher R . Continuous growth and differentiation of human myeloid leukemia cells in suspension culture Nature 1977 270: 347–349

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Gallagher R, Collins S, Trujillo J, McCredie K, Ahearn M, Tsai S, Metzgar R, Aulakh G, Ting R, Ruscetti F, Gallo R . Characterization of the continuous, differentiating myeloid cell line (HL-60) from a patient with acute promyelocytic leukemia Blood 1979 54: 713–733

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Dalton WT Jr, Ahearn MJ, McCredie KB, Freireich EJ, Stass SA, Trujillo JM . HL-60 cell line was derived from a patient with FAB-M2 and not FAB-M3 Blood 1988 71: 242–247

    PubMed  Google Scholar 

  61. 61

    Collins S, Groudine M . Amplification of endogenous myc-related DNA sequences in a human myeloid leukaemia cell line Nature 1982 298: 679–681

    CAS  PubMed  Google Scholar 

  62. 62

    Breitman T, Selonick S, Collins S . Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid Proc Natl Acad Sci USA 1980 77: 2936–2940

    CAS  Google Scholar 

  63. 63

    Collins S, Robertson K, Mueller L . Retinoic acid induced granulocytic differentiation of HL-60 myeloid leukemia cells is mediated directly through the retinoic acid receptor (RAR-alpha) Mol Cell Biol 1990 10: 2154–2163

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Westin EH, Wong-Staal F, Gelmann EP, Dalla-Favera R, Papas TS, Lautenberger JA, Eva A, Reddy EP, Tronick SR, Aaronson SA, Gallo RC . Expression of cellular homologues of retroviral onc genes in human hematopoietic cells Proc Natl Acad Sci USA 1982 79: 2490–2494

    CAS  PubMed  Google Scholar 

  65. 65

    Grosso LE, Pitot HC . Transcriptional regulation of c-myc during chemically induced differentiation of HL-60 cultures Cancer Res 1985 45: 847–850

    CAS  PubMed  Google Scholar 

  66. 66

    Bentley DL, Groudine M . A block to elongation is largely responsible for decreased transcription of c-myc in differentiated HL60 cells Nature 1986 321: 702–706

    CAS  PubMed  Google Scholar 

  67. 67

    Gowda SD, Koler RD, Bagby GC Jr . Regulation of C-myc expression during growth and differentiation of normal and leukemic human myeloid progenitor cells J Clin Invest 1986 77: 271–278

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Grandori C, Eisenman RN . Myc target genes Trends Biochem Sci 1997 22: 177–181

    CAS  Google Scholar 

  69. 69

    Dang CV . c-Myc target genes involved in cell growth, apoptosis, and metabolism Mol Cell Biol 1999 19: 1–11

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Ishida S, Shudo K, Takada S, Koike K . Transcription from the P2 promoter of human protooncogene myc is suppressed by retinoic acid through an interaction between the E2F element and its binding proteins Cell Growth Differ 1994 5: 287–294

    CAS  PubMed  Google Scholar 

  71. 71

    Roussel MF, Davis JN, Cleveland JL, Ghysdael J, Hiebert SW . Dual control of myc expression through a single DNA binding site targeted by ets family proteins and E2F-1 Oncogene 1994 9: 405–415

    CAS  PubMed  Google Scholar 

  72. 72

    Ishida S, Shudo K, Takada S, Koike K . A direct role of transcription factor E2F in c-myc gene expression during granulocytic and macrophage-like differentiation of HL60 cells Cell Growth Differ 1995 6: 229–237

    CAS  PubMed  Google Scholar 

  73. 73

    Zhang DE, Zhang P, Wang ND, Hetherington CJ, Darlington GJ, Tenen DG . Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice Proc Natl Acad Sci USA 1997 94: 569–574

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Wang X, Scott E, Sawyers CL, Friedman AD . C/EBPalpha bypasses granulocyte colony-stimulating factor signals to rapidly induce PU.1 gene expression, stimulate granulocytic differentiation, and limit proliferation in 32D cl3 myeloblasts Blood 1999 94: 560–571

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Radomska HS, Huettner CS, Zhang P, Cheng T, Scadden DT, Tenen DG . CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors Mol Cell Biol 1998 18: 4301–4314

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Johansen LM, Iwama A, Lodie TA, Sasaki K, Felsher DW, Golub TR, Tenen DG . c-Myc is a critical target for c/EBPalpha in granulopoiesis Mol Cell Biol 2001 21: 3789–3806

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Boudjelal M, Taneja R, Matsubara S, Bouillet P, Dolle P, Chambon P . Overexpression of Stra13, a novel retinoic acid-inducible gene of the basic helix–loop–helix family, inhibits mesodermal and promotes neuronal differentiation of P19 cells Genes Dev 1997 11: 2052–2065

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Sun H, Taneja R . Stra13 expression is associated with growth arrest and represses transcription through histone deacetylase (HDAC)-dependent and HDAC-independent mechanisms Proc Natl Acad Sci USA 2000 97: 4058–4063

    CAS  Google Scholar 

  79. 79

    Sun H, Lu B, Li RQ, Flavell RA, Taneja R . Defective T cell activation and autoimmune disorder in Stra13-deficient mice Nat Immunol 2001 2: 1040–1047

    CAS  Google Scholar 

  80. 80

    Landschulz WH, Johnson PF, Adashi EY, Graves BJ, McKnight SL . Isolation of a recombinant copy of the gene encoding C/EBP Genes Dev 1988 2: 786–800

    CAS  Google Scholar 

  81. 81

    Yamanaka R, Kim GD, Radomska HS, Lekstrom-Himes J, Smith LT, Antonson P, Tenen DG, Xanthopoulos KG . CCAAT/enhancer binding protein epsilon is preferentially up-regulated during granulocytic differentiation and its functional versatility is determined by alternative use of promoters and differential splicing Proc Natl Acad Sci USA 1997 94: 6462–6467

    CAS  Google Scholar 

  82. 82

    Chih DY, Chumakov AM, Park DJ, Silla AG, Koeffler HP . Modulation of mRNA expression of a novel human myeloid-selective CCAAT/enhancer binding protein gene (C/EBP epsilon) Blood 1997 90: 2987–2994

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Chumakov AM, Grillier I, Chumakova E, Chih D, Slater J, Koeffler HP . Cloning of the novel human myeloid-cell-specific C/EBP-epsilon transcription factor Mol Cell Biol 1997 17: 1375–1386

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Yamanaka R, Barlow C, Lekstrom-Himes J, Castilla LH, Liu PP, Eckhaus M, Decker T, Wynshaw-Boris A, Xanthopoulos KG . Impaired granulopoiesis, myelodysplasia, and early lethality in CCAAT/enhancer binding protein epsilon-deficient mice Proc Natl Acad Sci USA 1997 94: 13187–13192

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Gombart AF, Shiohara M, Kwok SH, Agematsu K, Komiyama A, Koeffler HP . Neutrophil-specific granule deficiency: homozygous recessive inheritance of a frameshift mutation in the gene encoding transcription factor CCAAT/enhancer binding protein-epsilon Blood 2001 97: 2561–2567

    CAS  PubMed  Google Scholar 

  86. 86

    Lekstrom-Himes JA, Dorman SE, Kopar P, Holland SM, Gallin JI . 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: 1847–1852

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Nakajima H, Ihle JN . Granulocyte colony-stimulating factor regulates myeloid differentiation through CCAAT/enhancer-binding protein epsilon Blood 2001 98: 897–905

    CAS  PubMed  Google Scholar 

  88. 88

    Park DJ, Chumakov AM, Vuong PT, Chih DY, Gombart AF, Miller WH Jr, Koeffler HP . CCAAT/enhancer binding protein epsilon is a potential retinoid target gene in acute promyelocytic leukemia treatment J Clin Invest 1999 103: 1399–1408

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Collins SJ, Ulmer J, Purton LE, Darlington G . Multipotent hematopoietic cell lines derived from C/EBPalpha(−/−) knockout mice display granulocyte macrophage-colony-stimulating factor, granulocyte- colony-stimulating factor, and retinoic acid-induced granulocytic differentiation Blood 2001 98: 2382–2388

    CAS  PubMed  Google Scholar 

  90. 90

    Krumlauf R . Hox genes in vertebrate development Cell 1994 78: 191–201

    CAS  Google Scholar 

  91. 91

    Magli MC, Barba P, Celetti A, De Vita G, Cillo C, Boncinelli E . Coordinate regulation of HOX genes in human hematopoietic cells Proc Natl Acad Sci USA 1991 88: 6348–6352

    CAS  Google Scholar 

  92. 92

    Lawrence HJ, Sauvageau G, Humphries HK, Largman C . The role of HOX homeobox genes in normal and leukemic hematopoiesis Stem Cells 1996 14: 281–291

    CAS  PubMed  Google Scholar 

  93. 93

    Sauvageau G, Thorsteinsdottir U, Eaves C, Lawrence HJ, Largman C, Lansdorp P, Humphries RK . Overexpression of HOX4B in hematopoietic cells causes the selective expansion of more primitive populations in vitro and in vivo Genes Dev 1995 9: 1753–1765

    CAS  Google Scholar 

  94. 94

    Lill MC, Fuller JF, Herzig R, Crooks GM, Gasson JC . The role of the homeobox gene, HOX B7, in human myelomonocytic differentiation Blood 1995 85: 692–697

    CAS  Google Scholar 

  95. 95

    Thorsteinsdottir U, Sauvageau G, Hough M, Dragowska W, Lansdorp P, Lawrence HJ, Largman C, Humphries RK . Overexpression of HOXA10 in murine hematopoietic cells perturbs both myeloid and lymphoid differentiation and leads to acute myeloid leukemia Mol Cell Biol 1997 17: 495–505

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Borrow J, Shearman AM, Stanton VP Jr, Becher R, Collins T, Williams AJ, Dube I, Katz F, Kwong YL, Morris C, Ohyashiki K, Toyama K, Rowley J, Housman DE . The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9 Nat Genet 1996 12: 159–167

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Nakamura T, Largaespada DA, Lee MP, Johnson LA, Ohyashiki K, Toyama K, Chen SJ, Willman CL, Chen IM, Feinberg AP, Jenkins NA, Copeland NG, Shaughnessy JD Jr . Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia Nat Genet 1996 12: 154–158

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Nakamura T, Largaespada D, Shaughnessy J, Jenkins N, Copeland N . Cooperative activation of Hoxa and Pbx1-related genes in murine myeloid leukemias Nature Genet 1996 12: 149–153

    CAS  PubMed  Google Scholar 

  99. 99

    Conlon RA . Retinoic acid and pattern formation in vertebrates Trends Genet 1995 11: 314–319

    CAS  PubMed  Google Scholar 

  100. 100

    Simeone A, Acampora D, Arcioni L, Andrews PW, Boncinelli E, Mavilio F . Sequential activation of HOX2 homeobox genes by retinoic acid in human embryonal carcinoma cells Nature 1990 346: 763–766

    CAS  Google Scholar 

  101. 101

    Langston AW, Gudas LJ . Identification of a retinoic acid responsive enhancer 3′ of the murine homeobox gene Hox-1.6 Mech Dev 1992 38: 217–227

    CAS  PubMed  Google Scholar 

  102. 102

    Langston A, Thompson J, Gudas L . Retinoic acid-responsive enhancers located 3′ of the Hox A and Hox B homeobox gene clusters J Biol Chem 1997 272: 2167–2175

    CAS  PubMed  Google Scholar 

  103. 103

    Ogura T, Evans RM . Evidence for two distinct retinoic acid response pathways for HOXB1 gene regulation Proc Natl Acad Sci USA 1995 92: 392–396

    CAS  PubMed  Google Scholar 

  104. 104

    Popperl H, Featherstone MS . Identification of a retinoic acid response element upstream of the murine Hox-4.2 gene Mol Cell Biol 1993 13: 257–265

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Sherr CJ, Roberts JM . Inhibitors of mammalian G1 cyclin-dependent kinases Genes Dev 1995 9: 1149–1163

    CAS  Google Scholar 

  106. 106

    Steinman RA, Hoffman B, Iro A, Guillouf C, Liebermann DA, el-Houseini ME . Induction of p21 (WAF-1/CIP1) during differentiation Oncogene 1994 9: 3389–3396

    CAS  Google Scholar 

  107. 107

    Jiang H, Lin J, Su ZZ, Collart FR, Huberman E, Fisher PB . Induction of differentiation in human promyelocytic HL-60 leukemia cells activates p21, WAF1/CIP1, expression in the absence of p53 Oncogene 1994 9: 3397–3406

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Liu M, Iavarone A, Freedman LP . Transcriptional activation of the human p21(WAF1/CIP1) gene by retinoic acid receptor. Correlation with retinoid induction of U937 cell differentiation J Biol Chem 1996 271: 31723–31728

    CAS  Google Scholar 

  109. 109

    Zhang H, Hannon GJ, Beach D . p21-containing cyclin kinases exist in both active and inactive states Genes Dev 1994 8: 1750–1758

    CAS  Google Scholar 

  110. 110

    LaBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, Fattaey A, Harlow E . New functional activities for the p21 family of CDK inhibitors Genes Dev 1997 11: 847–862

    CAS  Google Scholar 

  111. 111

    Taniguchi T, Endo H, Chikatsu N, Uchimaru K, Asano S, Fujita T, Nakahata T, Motokura T . Expression of p21(Cip1/Waf1/Sdi1) and p27(Kip1) cyclin-dependent kinase inhibitors during human hematopoiesis Blood 1999 93: 4167–4178

    CAS  PubMed  Google Scholar 

  112. 112

    Yaroslavskiy B, Watkins S, Donnenberg AD, Patton TJ, Steinman RA . Subcellular and cell-cycle expression profiles of CDK-inhibitors in normal differentiating myeloid cells Blood 1999 93: 2907–2917

    CAS  PubMed  Google Scholar 

  113. 113

    Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T, Hannon GJ . Radiation-induced cell cycle arrest compromised by p21 deficiency Nature 1995 377: 552–557

    CAS  PubMed  Google Scholar 

  114. 114

    Deng C, Zhang P, Harper JW, Elledge SJ, Leder P . Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control Cell 1995 82: 675–684

    CAS  Google Scholar 

  115. 115

    Leroy P, Nakshatri H, Chambon P . Mouse retinoic acid receptor alpha 2 isoform is transcribed from a promoter that contains a retinoic acid response element Proc Natl Acad Sci USA 1991 88: 10138–10142

    CAS  PubMed  Google Scholar 

  116. 116

    Zelent A . PCR cloning of N-terminal RAR isoforms and APL-associated PLZF-RAR alpha fusion proteins Meth Mol Biol 1998 89: 307–332

    CAS  Google Scholar 

  117. 117

    de The H, Vivanco-Ruiz MM, Tiollais P, Stunnenberg H, Dejean A . Identification of a retinoic acid responsive element in the retinoic acid receptor beta gene Nature 1990 343: 177–180

    CAS  Google Scholar 

  118. 118

    Sucov HM, Murakami KK, Evans RM . Characterization of an autoregulated response element in the mouse retinoic acid receptor type beta gene Proc Natl Acad Sci USA 1990 87: 5392–5396

    CAS  PubMed  Google Scholar 

  119. 119

    Zelent A, Mendelsohn C, Kastner P, Krust A, Garnier JM, Ruffenach F, Leroy P, Chambon P . Differentially expressed isoforms of the mouse retinoic acid receptor beta generated by usage of two promoters and alternative splicing Embo J 1991 10: 71–81

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Giguere V, Ong ES, Segui P, Evans RM . Identification of a receptor for the morphogen retinoic acid Nature 1987 330: 624–629

    CAS  Google Scholar 

  121. 121

    Petkovich M, Brand NJ, Krust A, Chambon P . A human retinoic acid receptor which belongs to the family of nuclear receptors Nature 1987 330: 444–450

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122

    Labrecque J, Bhat PV, Lacroix A . Purification and partial characterization of a rat kidney aldehyde dehydrogenase that oxidizes retinal to retinoic acid Biochem Cell Biol 1993 71: 85–89

    CAS  PubMed  Google Scholar 

  123. 123

    Jones RJ, Collector MI, Barber JP, Vala MS, Fackler MJ, May WS, Griffin CA, Hawkins AL, Zehnbauer BA, Hilton J, Colvin OM, Sharkis SJ . Characterization of mouse lymphohematopoietic stem cells lacking spleen colony-forming activity Blood 1996 88: 487–491

    CAS  PubMed  Google Scholar 

  124. 124

    Storms RW, Trujillo AP, Springer JB, Shah L, Colvin OM, Ludeman SM, Smith C . Isolation of primitive human hematopoietic progenitors on the basis of aldehyde dehydrogenase activity Proc Natl Acad Sci USA 1999 96: 9118–9123

    CAS  PubMed  Google Scholar 

  125. 125

    Ferrara FF, Fazi F, Bianchini A, Padula F, Gelmetti V, Minucci S, Mancini M, Pelicci PG, Lo Coco F, Nervi C . Histone deacetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia Cancer Res 2001 61: 2–7

    Google Scholar 

  126. 126

    Nakamaki T, Hino K, Yokoyama A, Hisatake J, Tomoyasu S, Honma Y, Hozumi M, Tsuruoka N . Effect of cytokines on the proliferation and differentiation of acute promyelocytic leukemia cells: possible relationship to the development of ‘retinoic acid syndrome’ Anticancer Res 1994 14: 817–823

    CAS  PubMed  Google Scholar 

  127. 127

    Darnell JE Jr . STATs and gene regulation Science 1997 277: 1630–1635

    CAS  Google Scholar 

  128. 128

    Ihle JN . STATs: signal transducers and activators of transcription Cell 1996 84: 331–334

    CAS  Google Scholar 

  129. 129

    Ehret GB, Reichenbach P, Schindler U, Horvath CM, Fritz S, Nabholz M, Bucher P . DNA binding specificity of different STAT proteins. Comparison of in vitro specificity with natural target sites J Biol Chem 2001 276: 6675–6688

    CAS  PubMed  Google Scholar 

  130. 130

    Si J, Collins S . IL-3 induced enhancement of RA receptor activity is mediated through Stat5, which physically associates with retinoic acid receptors in an IL-3 dependent manner Blood (in press)

  131. 131

    Olsson IL, Breitman TR . Induction of differentiation of the human histiocytic lymphoma cell line U-937 by retinoic acid and cyclic adenosine 3′:5′-monophosphate-inducing agents Cancer Res 1982 42: 3924–3927

    CAS  Google Scholar 

  132. 132

    Olsson IL, Breitman TR, Gallo RC . Priming of human myeloid leukemic cell lines HL-60 and U-937 with retinoic acid for differentiating effects of cyclic adenosine 3′:5′-monophosphate-inducing agents and a T-lymphocyte-derived differentiation factor Cancer Res 1982 42: 3928–3933

    CAS  PubMed  Google Scholar 

  133. 133

    Ruchaud S, Duprez E, Gendron MC, Houge G, Genieser HG, Jastorff B, Doskeland SO, Lanotte M . Two distinctly regulated events, priming and triggering, during retinoid-induced maturation and resistance of NB4 promyelocytic leukemia cell line Proc Natl Acad Sci USA 1994 91: 8428–8432

    CAS  Google Scholar 

  134. 134

    Benoit G, Altucci L, Flexor M, Ruchaud S, Lillehaug J, Raffelsberger W, Gronemeyer H, Lanotte M . RAR-independent RXR signaling induces t(15;17) leukemia cell maturation Embo J 1999 18: 7011–7018

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Rochette-Egly C, Oulad-Abdelghani M, Staub A, Pfister V, Scheuer I, Chambon P, Gaub MP . Phosphorylation of the retinoic acid receptor-alpha by protein kinase A Mol Endocrinol 1995 9: 860–871

    CAS  PubMed  Google Scholar 

  136. 136

    Rowan BG, Garrison N, Weigel NL, O'Malley BW . 8-Bromo-cyclic AMP induces phosphorylation of two sites in SRC-1 that facilitate ligand-independent activation of the chicken progesterone receptor and are critical for functional cooperation between SRC-1 and CREB binding protein Mol Cell Biol 2000 20: 8720–8730

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Melnick A, Licht JD . Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia Blood 1999 93: 3167–3215

    CAS  Google Scholar 

  138. 138

    Zelent A, Guidez F, Melnick A, Waxman S, Licht JD . Translocations of the RARalpha gene in acute promyelocytic leukemia Oncogene 2001 20: 7186–7203

    CAS  PubMed  Google Scholar 

  139. 139

    Glass CK, Rosenfeld MG . The coregulator exchange in transcriptional functions of nuclear receptors Genes Dev 2000 14: 121–141

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Grignani F, De Matteis S, Nervi C, Tomassoni L, Gelmetti V, Cioce M, Fanelli M, Ruthardt M, Ferrara F, Zamir I, Seiser C, Grignani M, Lazar M, Minucci S, Pelicci PG . Fusion proteins of the retinoic acid receptor-a recruit histone deacetylase in promyelocytic leukemia Nature 1998 319: 815–818

    Google Scholar 

  141. 141

    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-RARalpha underlie molecular pathogenesis and treatment of acute promyelocytic leukemia Blood 1998 91: 2634–2642

    CAS  Google Scholar 

  142. 142

    Chen Z, Guidez F, Rousselot P, Agadir A, Chen SJ, Wang ZY, Degos L, Zelent A, Waxman S, Chomienne C . PLZF-RAR alpha fusion proteins generated from the variant t(11;17)(q23;q21) translocation in acute promyelocytic leukemia inhibit ligand-dependent transactivation of wild-type retinoic acid receptors Proc Natl Acad Sci USA 1994 91: 1178–1182

    CAS  Google Scholar 

  143. 143

    Licht JD, Chomienne C, Goy A, Chen A, Scott AA, Head DR, Michaux JL, Wu Y, DeBlasio A, Miller WH Jr . Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17) Blood 1995 85: 1083–1094

    CAS  Google Scholar 

  144. 144

    Mu ZM, Chin KV, Liu JH, Lozano G, Chang KS . PML, a growth suppressor disrupted in acute promyelocytic leukemia Mol Cell Biol 1994 14: 6858–6867

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    Quignon F, De Bels F, Koken M, Feunteun J, Ameisen JC, de Thé H . PML induces a novel caspase-independent death process Nat Genet 1998 20: 259–265

    CAS  Google Scholar 

  146. 146

    Wang ZG, Ruggero D, Ronchetti S, Zhong S, Gaboli M, Rivi R, Pandolfi PP . PML is essential for multiple apoptotic pathways Nat Genet 1998 20: 266–272

    CAS  Google Scholar 

  147. 147

    Guo A, Salomoni P, Luo J, Shih A, Zhong S, Gu W, Paolo Pandolfi P . The function of PML in p53-dependent apoptosis Nat Cell Biol 2000 2: 730–736

    CAS  PubMed  Google Scholar 

  148. 148

    Salomoni P, Pandolfi PP . The role of PML in tumor suppression Cell 2002 108: 165–170

    CAS  PubMed  Google Scholar 

  149. 149

    Shaknovich R, Yeyati PL, Ivins S, Melnick A, Lempert C, Waxman S, Zelent A, Licht JD . The promyelocytic leukemia zinc finger protein affects myeloid cell growth, differentiation, and apoptosis Mol Cell Biol 1998 18: 5533–5545

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150

    Morosetti R, Grignani F, Liberatore C, Pelicci P, Schiller G, Kizaki M, Bartram CCM, Koeffler H . Infrequent alterations of the RAR alpha gene in acute myelogenous leukemias, retinoic acid-resistant acute promyelocytic leukemias, myelodysplastic syndromes and cell lines Blood 1996 87: 4399–4403

    CAS  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to SJ Collins.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Collins, S. The role of retinoids and retinoic acid receptors in normal hematopoiesis. Leukemia 16, 1896–1905 (2002). https://doi.org/10.1038/sj.leu.2402718

Download citation

Keywords

  • retinoic acid receptors
  • myelopoiesis
  • acute promyelocytic leukemia
  • retinoids

Further reading

Search

Quick links