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
  • Published:

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

References

  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  PubMed Central  Google Scholar 

  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  Google Scholar 

  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  Google Scholar 

  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. 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. 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  PubMed  Google Scholar 

  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. 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. 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  Google Scholar 

  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  Google Scholar 

  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

    PubMed  Google Scholar 

  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  PubMed  Google Scholar 

  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  PubMed  PubMed Central  Google Scholar 

  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  PubMed  Google Scholar 

  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  Google Scholar 

  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. 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. 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  PubMed  Google Scholar 

  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  PubMed  Google Scholar 

  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. 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  Google Scholar 

  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  Google Scholar 

  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  Google Scholar 

  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. 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  PubMed  Google Scholar 

  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  PubMed  PubMed Central  Google Scholar 

  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. 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. 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. 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. 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  Google Scholar 

  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  Google Scholar 

  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  Google Scholar 

  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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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  PubMed  Google Scholar 

  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. 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  PubMed Central  Google Scholar 

  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  PubMed Central  Google Scholar 

  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  PubMed  Google Scholar 

  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. 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. 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. 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  PubMed  Google Scholar 

  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  PubMed  Google Scholar 

  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  Google Scholar 

  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  Google Scholar 

  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. 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. 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  PubMed  PubMed Central  Google Scholar 

  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. 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  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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. 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. 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. 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. 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. 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  Google Scholar 

  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. 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. 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. 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  PubMed  PubMed Central  Google Scholar 

  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  PubMed  Google Scholar 

  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  PubMed  Google Scholar 

  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  PubMed  PubMed Central  Google Scholar 

  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  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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  PubMed  PubMed Central  Google Scholar 

  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. 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  PubMed  Google Scholar 

  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  PubMed  Google Scholar 

  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. 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  Google Scholar 

  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  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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  PubMed  Google Scholar 

  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. 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. 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  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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  PubMed  Google Scholar 

  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  Google Scholar 

  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  PubMed  Google Scholar 

  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  PubMed  Google Scholar 

  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  PubMed  Google Scholar 

  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. 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. 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. 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  PubMed  Google Scholar 

  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  PubMed Central  Google Scholar 

  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. 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  PubMed  Google Scholar 

  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  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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  Google Scholar 

  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. 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. 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  PubMed Central  Google Scholar 

  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

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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. 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. 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  PubMed  Google Scholar 

  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. 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  PubMed  PubMed Central  Google Scholar 

  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. 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. 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. 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  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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. 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  PubMed  Google Scholar 

  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  PubMed  PubMed Central  Google Scholar 

  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  PubMed  Google Scholar 

  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. 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  PubMed  Google Scholar 

  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  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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. 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

Authors and Affiliations

Authors

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

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402718

Keywords

This article is cited by

Search

Quick links