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The biology of acute promyelocytic leukemia

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Abstract

Acute promyelocytic leukemia (APL) is a disease associated with fusion oncoproteins invariably involving the retinoic acid receptor (Rarα). Retinoic acid induces differentiation in APL cells and is successfully used in conjunction with chemotherapy to treat and cure a significant percentage of patients with APL. APL is also a model for disruption of normal retinoid-mediated transcription resulting in blocked differentiation. The study of the molecular mechanisms of APL oncogenesis has revealed novel interactions between fusion oncoproteins and transcriptional coregulators, already leading to new treatment strategies.

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References and Recommended Reading

  1. Tallman MS: The thrombophilic state in acute promyelocytic leukemia. Semin Thromb Hemost 1999, 25:209–215.

    PubMed  CAS  Google Scholar 

  2. Huang ME, Ye YC, Chen SR, et al.: Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988, 72:567–572.

    PubMed  CAS  Google Scholar 

  3. Fenaux P, Le Deley MC, Castaigne S, et al.: Effect of all-trans retinoic acid in newly diagnosed acute promyelocytic leukemia: results of a multicenter randomized trial. Blood 1993, 82:3241–3249.

    PubMed  CAS  Google Scholar 

  4. Tallman MS, Andersen JW, Schiffer CA, et al.: All-trans retinoic acid in acute promyelocytic leukemia. N Engl J Med 1997, 337:1021–1028.

    Article  PubMed  CAS  Google Scholar 

  5. Warrell RP Jr, Frankel SR, Miller WH Jr, et al.: Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med 1991, 324:1385–1393.

    Article  PubMed  Google Scholar 

  6. Castaigne S, Chomienne C, Daniel MT, et al.: All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood 1990, 76:1704–1709.

    PubMed  CAS  Google Scholar 

  7. Fenaux P, Chastang C, Degos L: Treatment of newly diagnosed acute promyelocytic leukemia (APL) by a combination of all-trans retinoic acid (ATRA) and chemotherapy. French APL Group. Leukemia 1994, 8(suppl 2):S42-S47.

    PubMed  Google Scholar 

  8. Sanz MA, Lo Coco F, Martin G, et al.: Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood 2000, 96:1247–1253.

    PubMed  CAS  Google Scholar 

  9. Estey E, Thall PF, Pierce S, et al.: Treatment of newly diagnosed acute promyelocytic leukemia without cytarabine. J Clin Oncol 1997, 15:483–490.

    PubMed  CAS  Google Scholar 

  10. Rowley JD, Golomb HM, Dougherty C: 15;17 translocation: a consistent chromosomal change in acute promyelocytic leukemia. Lancet 1977, 1:549.

    Article  PubMed  CAS  Google Scholar 

  11. Mattei MG, Petkovich M, Mattei JF, et al.: Mapping of the human retinoic acid receptor to the q21 band of chromosome 17. Human Genet 1988, 80:186–187.

    Article  CAS  Google Scholar 

  12. Miller WH Jr, Warrell RP Jr, Frankel SR, et al.: Novel retinoic acid receptor-a transcripts in acute promyelocytic leukemia responsive to all-trans-retinoic acid. J Natl Cancer Inst 1990, 32:1932–1933.

    Article  Google Scholar 

  13. de The H, Chomienne C, Lanotte M, et al.: The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature 1990, 347:558–561.

    Article  PubMed  Google Scholar 

  14. Borrow J, Goddard AD, Sheer D, Solomon E: Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17. Science 1990, 249:1577–1580.

    Article  PubMed  CAS  Google Scholar 

  15. de TheH, Lavau C, Marchio A, et al.: The PML-RAR alpha 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 

  16. Kakizuka A, Miller WH Jr, Umesono K, et al.: 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.

    Article  PubMed  CAS  Google Scholar 

  17. Pandolfi PP, Grignani F, Alcalay M, et al.: Structure and origin of the acute promyelocytic leukemia myl/RARa cDNA and characterization of its retinoid-binding and transactivation properties. Oncogene 1991, 6:1285–1292.

    PubMed  CAS  Google Scholar 

  18. He L-Z, Tribioli C, Rivi R, et al.: Acute leukemia with promyelocytic features in PML/RARa transgenic mice. Proc Natl Acad Sci U S A 1997, 94:5302–5307.

    Article  PubMed  CAS  Google Scholar 

  19. Grisolano J, Wesselschmidt R, Pelicci PG, Ley T: Altered myeloid development and acute leukemia in transgenic mice expressing PML-RARa under control of cathepsin G regulatory sequences. Blood 1997, 89:376–387.

    PubMed  CAS  Google Scholar 

  20. Brown D, Kogan S, Lagasse E, et al.: A PML/RAR alpha transgene initiates murine acute promyelocytic leukemia. Proc Natl Acad Sci U S A 1997, 94:2551–2556.

    Article  PubMed  CAS  Google Scholar 

  21. Grignani F, Valtieri M, Gabbianelli M, et al.: PML/RAR alpha fusion protein expression in normal human hematopoietic progenitors dictates myeloid commitment and the promyelocytic phenotype. Blood 2000, 96:1531–1537.

    PubMed  CAS  Google Scholar 

  22. Chen Z, Brand NJ, Chen A, et al.: Fusion between a novel Kruppel-like zinc finger gene and the retinoic acid receptor-a locus due to a variant t(11;17) translocation associated with acute promyelocytic leukaemia. EMBO J 1993, 12:1161–1167.

    PubMed  CAS  Google Scholar 

  23. Redner RL, Rush EA, Faas S, et al.: The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor fusion. Blood 1996, 87:882–886.

    PubMed  CAS  Google Scholar 

  24. Wells RA, Catzavelos C, Kamel-Reid S: Fusion of retinoic acid receptor a to NuMA, the nuclear mitotic apparatus protein, by a variant translocation in acute promyelocytic leukaemia. Nat Genet 1997, 17:109–113.

    Article  PubMed  CAS  Google Scholar 

  25. Arnould C, Philippe C, Bourdon V, et al.: The signal transducer and activator of transcription STAT5b gene is a new partner of retinoic acid receptor a in acute promyelocytic-like leukaemia. Human Mol Genet 1999, 8:1741–1749.

    Article  CAS  Google Scholar 

  26. Lin RJ, Evans RM: Acquisition of oncogenic potential by RAR chimeras in acute promyelocytic leukemia through formation of homodimers. Mol Cell 2000, 5:821–830. See annotation below for [27].

    Article  PubMed  CAS  Google Scholar 

  27. Minucci S, Maccarana M, Cioce M, et al.: Oligomerization of RAR and AML1 transcription factors as a novel mechanism of oncogenic activation. Mol Cell 2000, 5:811–820. Both of these articles provide novel data for common properties required of RARa fusion partners to induce the APL phenotype. The importance of interactions with corepressors is highlighted.

    Article  PubMed  CAS  Google Scholar 

  28. Nagy L, Kao H-Y, Chakravarti D, et al.: Nuclear receptor repression mediated by a complex containing SMRT, mSin3A, and histone deacetylase. Cell 1997, 89:373–380.

    Article  PubMed  CAS  Google Scholar 

  29. Heinzel T, Lavinsky RM, Mullen TM, et al.: A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature 1997, 387:43–48.

    Article  PubMed  CAS  Google Scholar 

  30. Stuurman N, Floore A, Middelkoop E, et al.: PML shuttles between nuclear bodies and the cytoplasm. Cell Mol Biol Lett 1997, 2:137–150.

    CAS  Google Scholar 

  31. Dyck JA, Maul GG, Miller WH Jr, et al.: A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein. Cell 1994, 76:333–343.

    Article  PubMed  CAS  Google Scholar 

  32. van Driel R, Humbel B, de Jong L: The nucleus: a black box being opened. J Cell Biochem 1991, 47:311–316.

    Article  PubMed  Google Scholar 

  33. Borden KL, Boddy MN, Lally J, et al.: The solution structure of the RING finger domain from the acute promyelocytic leukaemia proto-oncoprotein PML. EMBO J 1995, 14:1532–1541.

    PubMed  CAS  Google Scholar 

  34. Le XF, Yang P, Chang KS: Analysis of the growth and transformation suppressor domains of promyelocytic leukemia gene, PML. J Biol Chem 1996, 271:130–136.

    Article  PubMed  CAS  Google Scholar 

  35. Mu ZM, Chin KV, Liu JH, et al.: PML, a growth suppressor disrupted in acute promyelocytic leukemia. Mol Cell Biol 1994, 14:6858–6867.

    PubMed  CAS  Google Scholar 

  36. Ahn MJ, Nason-Burchenal K, Moasser MM, Dmitrovsky E: Growth suppression of acute promyelocytic leukemia cells having increased expression of the non-rearranged alleles: RAR alpha or PML. Oncogene 1995, 10:2307–2314.

    PubMed  CAS  Google Scholar 

  37. Wang Z, Delva L, Gaboli M, et al.: Role of PML in cell growth and the retinoic acid pathway. Science 1998, 279:1547–1551.

    Article  PubMed  CAS  Google Scholar 

  38. Wang Z, Ruggero D, Ronchetti S, et al.: PML is essential for multiple apoptotic pathways. Nat Genet 1998, 20:266–272.

    Article  PubMed  CAS  Google Scholar 

  39. Pearson M, Carbone R, Sebastiani C, et al.: PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 2000, 406:207–210. The authors report a novel and potentially important action of PML.

    Article  PubMed  CAS  Google Scholar 

  40. Doucas V, Tini M, Egan DA, Evans RM: Modulaton fo CREB binding protein function by the promyelocytic (PML) oncoprotein suggests a role for nuclear bodies in hormone signaling. Proc Natl Acad Sci U S A 1999, 96:2627–2632.

    Article  PubMed  CAS  Google Scholar 

  41. Kastner P, Perez A, Lutz Y, et al.: 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.

    PubMed  CAS  Google Scholar 

  42. Weis K, Rambaud S, Lavau C, et al.: Retinoic acid regulates aberrant nuclear localization of PML-RARa in acute promyelocytic leukemia cells. Cell 1994, 76:345–356.

    Article  PubMed  CAS  Google Scholar 

  43. Lin RJ, Nagy L, Inoue S, et al.: Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature 1998, 391:811–814. See annotation below for reference [44].

    Article  PubMed  CAS  Google Scholar 

  44. Grignani F, De Matteis S, Nervi C, et al.: Fusion proteins of the retinoic acid receptor-a recruit histone deacetylase in promyelocytic leukaemia. Nature 1998, 391:815–818. These two reports show the correlation between aberrant associations of nuclear coregulators of transcription and the differentiation block of APL. They form the basis for current attempts to reverse retinoid resistance by modulation of transcription.

    Article  PubMed  CAS  Google Scholar 

  45. Raelson JV, Nervi C, Rosenauer A, et al.: The PML/RARα oncoprotein is a direct molecular target of retinoic acid in acute promyelocytic leukemia cells. Blood 1996, 88:2826–2832.

    PubMed  CAS  Google Scholar 

  46. Naoe T, Yoshida H, Kitamura K, et al.: Delayed or insufficient restoration of PML and PML-RARa subcellular localization after exposure in vitro to retinoic acids in all-trans retinoic acid resistant APL cells. Leukemia 1995, 9:1610–1611.

    PubMed  CAS  Google Scholar 

  47. Nason-Burchenal K, Takle G, Pace U, et al.: Targeting the PML/ RAR alpha translocation product triggers apoptosis in promyelocytic leukemia cells. Oncogene 1998, 17:1759–1768.

    Article  PubMed  CAS  Google Scholar 

  48. Delva L, Cornic M, Balitrand N, et al.: Resistance to all-trans retinoic acid (ATRA) therapy in relapsing acute promyelocytic leukemia: study of in vitro ATRA sensitivity and cellular retinoic acid binding protein levels in leukemic cells. Blood 1993, 82:2175–2181.

    PubMed  CAS  Google Scholar 

  49. Miller WH Jr, Reyno LM, Loewen GR, et al.: A phase I-II study of 9-cis retinoic acid and interferon-alpha2b in patients with advanced renal cell carcinoma: an NCIC Clinical Trials Group study. Ann Oncol 2000, 11:1–3.

    Article  Google Scholar 

  50. Miller WH Jr, Jakubowski A, Tong WP, et al.: 9-cis retinoic acid induces complete remission but does not reverse clinically acquired retinoid resistance in acute promyelocytic leukemia. Blood 1995, 85:3021–3027.

    PubMed  CAS  Google Scholar 

  51. Ding W, Li Y, Nobile LM, et al.: Leukemic cellular retinoic acid resistance and missense mutations in the PML-RARa fusion gene after relapse of acute promyelocytic leukemia from treatment with all-trans retinoic acid and intensive chemotherapy. Blood 1998, 92:1172–1183. The first report of a stable genetic change causing clinical resistance to retinoic acid in APL. This confirms previous reports of similar mutations in cellular models of retinoic acid resistance.

    PubMed  CAS  Google Scholar 

  52. Imaizumi M, Suzuki H, Yoshinari M, et al.: Mutations in the E-domain of RARa portion of the PML/RARa chimeric gene may confer clinical resistance to all-trans retinoic acid in acute promyelocytic leukemia. Blood 1998, 92:374–382.

    PubMed  CAS  Google Scholar 

  53. Shao W, Benedetti L, Lamph WW, et al.: A retinoid-resistant APL subclone expresses a dominant negative PML-RARα mutation. Blood 1997, 89:4282–4289.

    PubMed  CAS  Google Scholar 

  54. Côté S, Zhou D, Bianchini A, et al.: Altered ligand binding and transcriptional regulation by mutations in the PML/RAR ligand-binding domain arising in retinoic-acid-resistant patients with acute promyelocytic leukemia. Blood 2000, 96:3200–3208.

    PubMed  Google Scholar 

  55. Gelmetti V, Zhang J, Fanelli M, et al.: Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. Mol Cell Biol 1998, 18:7185–7191.

    PubMed  CAS  Google Scholar 

  56. Guidez F, Petrie K, Ford AM, et al.: Recruitment of the nuclear receptor corepressor N-CoR by the TEL moiety of the childhood leukemia-associated TEL-AML1 oncoprotein. Blood 2000, 96:2557–2561.

    PubMed  CAS  Google Scholar 

  57. Cheng G, Zhu X, Men X, et al.: Distinct leukemia phenotypes in transgenic mice and different corepressor interactions generated by promyelocytic leukemia variant fusion genes PLZF-RAR alpha and NPM-RAR alpha. Proc Natl Acad Sci U S A 1999, 96:6318–6323.

    Article  PubMed  CAS  Google Scholar 

  58. He L-Z, Merghoub T, Pandolfi PP: In vivo analysis of the molecular pathogenesis of acute promyelocytic leukemia in the mouse and its therapeutic implications. Oncogene 1999, 18:5278–5292.

    Article  PubMed  CAS  Google Scholar 

  59. He L, Guidez F, Tribioli C, et al.: Distinct interactions of PML-RAR alpha and PLZF-RAR alpha with co-repressors determine differential responses to RA in APL. Nat Genet 1998, 18:126–135.

    Article  PubMed  CAS  Google Scholar 

  60. Kogan SC, Hong SH, Shultz DB, et al.: Leukemia initiated by PMLRARalpha: the PML domain plays a critical role while retinoic acid-mediated transactivation is dispensable. Blood 2000, 95:1541–1550. The authors describe a mouse model of APL showing that a mutation in PML-RARα can confer in vivo resistance to retinoids. Similar mouse models may prove to be useful tools to dissect the molecular biology of the malignancy.

    PubMed  CAS  Google Scholar 

  61. Warrell RP Jr, He L, Richon V, et al.: Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Natl Cancer Inst 1998, 90:1621–1625. Pharmacologic inhibition of a mechanism of transcriptional repression was shown to produce a dramatic reversal of retinoid resistance in a patient with APL.

    Article  PubMed  CAS  Google Scholar 

  62. Shen ZX, Chen GQ, Ni JH, et al.: Use of arsenic trioxide in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 1997, 89:3354–3360.

    PubMed  CAS  Google Scholar 

  63. Shao W, Fanelli M, Ferrara FF, et al.: Arsenic trioxide as an inducer of apoptosis and loss of PML-RARα protein in acute promyelocytic leukemia cells. J Nat Cancer Inst 1998, 90:124–133.

    Article  PubMed  CAS  Google Scholar 

  64. Chen GQ, Shi XG, Tang W, et al.: Use of arsenic trioxide in the treatment of acute promyelocytic leukemia (APL): I. arsenic trioxide exerts dose-dependent dual effects on APL cells. Blood 19997, 89:3345–3353.

    Google Scholar 

  65. Soignet SL, Maslak P, Wang Z, et al.: Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 1998, 339:1341–1348. This article confirms the dramatic clinical activity of arsenical agents in APL, including activity in patients who have failed multiple conventional therapies.

    Article  PubMed  CAS  Google Scholar 

  66. Chen G, Zhu J, Shi X, et al.: In vitro studies on cellular and molecular mechanisms of arsenic trioxide in the treatment of acute promyelocytic leukemia: arsenic trioxide induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML-RARα/PML proteins. Blood 1996, 88:1052–1061.

    PubMed  CAS  Google Scholar 

  67. Jing Y, Dai J, Chalmers-Redman RME, et al.: Arsenic troxide selectively induces acute promyelocytic leukemia cell apoptosis via a hydrogen peroxide-dependent pathway. Blood 1999, 94:2102–2111.

    PubMed  CAS  Google Scholar 

  68. Chen Y, Lin-Shiau S, Lin J: Involvement of reactive oxygen species and caspase 3 activation in arsenite-induced apoptosis. J Cell Physiol 1998, 177:324–333.

    Article  PubMed  CAS  Google Scholar 

  69. Dai J, Weinberg RS, Waxman S, Jing Y: Malignant cells can be sensitized to undergo growth inhibition and apoptosis by arsenic trioxide through modulation of the glutathione redox system. Blood 1999, 93:268–277.

    PubMed  CAS  Google Scholar 

  70. Lallemand-Breitenbach V, Marie-Claude G, Janin A, et al.: Retinoic acid and arsenic synergize to eradicate leukemic cells in a mouse model of acute promyelocytic leukemia. J Exp Med 1999, 189:1043–1052.

    Article  PubMed  CAS  Google Scholar 

  71. Rego EM, He LZ, Warrell RP Jr, et al.: Retinoic acid (RA) and As2O3 treatment in transgenic models of acute promyelocytic leukemia (APL) unravel the distinct nature of the leukemogenic process induced by the PML-RARalpha and PLZF-RARalpha oncoproteins. Proc Natl Acad Sci U S A 2000, 97:10173–10178.

    Article  PubMed  CAS  Google Scholar 

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  1. Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Cote Ste. Catherine Road, 3755, Montreal, Quebec, Canada

    Koren K. Mann PhD, Wenlin Shao PhD & Wilson H. Miller Jr MD, PhD

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  1. Koren K. Mann PhD
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Mann, K.K., Shao, W. & Miller, W.H. The biology of acute promyelocytic leukemia. Curr Oncol Rep 3, 209–216 (2001). https://doi.org/10.1007/s11912-001-0052-1

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