Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Molecular biology of acute promyelocytic leukemia

Wendy Stock, MD
Michael J Thirman, MD
Section Editor
Richard A Larson, MD
Deputy Editor
Alan G Rosmarin, MD


Acute myeloid leukemia (AML) refers to a group of hematopoietic neoplasms involving cells committed to the myeloid lineage. Acute promyelocytic leukemia (APL) is a biologically and clinically distinct variant of AML. In the World Health Organization classification system, APL is classified as acute promyelocytic leukemia with PML-RARA; it was previously classified as AML-M3 in the older French-American-British (FAB) classification system [1,2]. (See "Classification of acute myeloid leukemia".)

The cytogenetic hallmark of APL is a translocation involving RARA, the retinoic acid receptor alpha locus on chromosome 17 [3]. The vast majority of cases of APL contain t(15;17)(q24.1;q21.1). However, several variant translocations involving RARA have been identified, including t(11;17) and t(5;17) [4-6], and distinguishing between these translocations is important because patients with the variant translocation t(11;17) are almost invariably resistant to all-trans retinoic acid (ATRA) [4,5,7]. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults" and "Initial treatment of acute promyelocytic leukemia in adults".)

The molecular biology of APL will be discussed here. The molecular biology of acute myeloid leukemias other than APL and of ALL is discussed separately. (See "Pathogenesis of acute myeloid leukemia" and "Cytogenetics and molecular genetics in acute lymphoblastic leukemia" and "Molecular genetics of acute myeloid leukemia".)


Retinoic acid (RA) is a critical ligand in the differentiation of multiple tissues, mediated through binding to a retinoic acid receptor (RAR). RARs belong to the nuclear steroid/thyroid hormone receptor superfamily. Of the three RAR isoforms, RAR alpha is expressed primarily in hematopoietic cells.

RAR alpha is a member of a family of retinoid-binding transcription factors (including RXR) that regulate gene expression. RAR alpha contains discrete functional domains, including an amino terminal transcriptional activation domain, and DNA-binding, dimerization, and retinoid-binding domains. RAR alpha heterodimerizes with retinoid X receptor (RXR), and binds to RA-responsive elements to regulate transcription of target genes [7].

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Aug 10, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Swerdlow SH, Campo E, Harris NL, et al. (Eds), IARC Press, Lyon 2008.
  2. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127:2391.
  3. de Thé 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.
  4. Collins SJ. Acute promyelocytic leukemia: relieving repression induces remission. Blood 1998; 91:2631.
  5. 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.
  6. Grimwade D. The pathogenesis of acute promyelocytic leukaemia: evaluation of the role of molecular diagnosis and monitoring in the management of the disease. Br J Haematol 1999; 106:591.
  7. Grignani F, Fagioli M, Alcalay M, et al. Acute promyelocytic leukemia: from genetics to treatment. Blood 1994; 83:10.
  8. Guidez F, Ivins S, Zhu J, et al. 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.
  9. Mueller BU, Pabst T, Fos J, et al. ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression. Blood 2006; 107:3330.
  10. Breitman TR, Collins SJ, Keene BR. Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acid. Blood 1981; 57:1000.
  11. Robertson KA, Emami B, Mueller L, Collins SJ. Multiple members of the retinoic acid receptor family are capable of mediating the granulocytic differentiation of HL-60 cells. Mol Cell Biol 1992; 12:3743.
  12. 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.
  13. Warrell RP Jr, de Thé H, Wang ZY, Degos L. Acute promyelocytic leukemia. N Engl J Med 1993; 329:177.
  14. Liu TX, Zhang JW, Tao J, et al. Gene expression networks underlying retinoic acid-induced differentiation of acute promyelocytic leukemia cells. Blood 2000; 96:1496.
  15. Cassinat B, Chevret S, Zassadowski F, et al. In vitro all-trans retinoic acid sensitivity of acute promyelocytic leukemia blasts: a novel indicator of poor patient outcome. Blood 2001; 98:2862.
  16. Altucci L, Rossin A, Raffelsberger W, et al. Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumor-selective death ligand TRAIL. Nat Med 2001; 7:680.
  17. Nasr R, Lallemand-Breitenbach V, Zhu J, et al. Therapy-induced PML/RARA proteolysis and acute promyelocytic leukemia cure. Clin Cancer Res 2009; 15:6321.
  18. Grimwade D, Biondi A, Mozziconacci MJ, et al. Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party. Groupe Français de Cytogénétique Hématologique, Groupe de Français d'Hematologie Cellulaire, UK Cancer Cytogenetics Group and BIOMED 1 European Community-Concerted Action "Molecular Cytogenetic Diagnosis in Haematological Malignancies". Blood 2000; 96:1297.
  19. de Thé H, 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.
  20. 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.
  21. Choi YH, Bernardi R, Pandolfi PP, Benveniste EN. The promyelocytic leukemia protein functions as a negative regulator of IFN-gamma signaling. Proc Natl Acad Sci U S A 2006; 103:18715.
  22. Weis K, Rambaud S, Lavau C, et al. Retinoic acid regulates aberrant nuclear localization of PML-RAR alpha in acute promyelocytic leukemia cells. Cell 1994; 76:345.
  23. 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.
  24. Zhu J, Koken MH, Quignon F, et al. Arsenic-induced PML targeting onto nuclear bodies: implications for the treatment of acute promyelocytic leukemia. Proc Natl Acad Sci U S A 1997; 94:3978.
  25. Maul GG, Negorev D, Bell P, Ishov AM. Review: properties and assembly mechanisms of ND10, PML bodies, or PODs. J Struct Biol 2000; 129:278.
  26. Guo A, Salomoni P, Luo J, et al. The function of PML in p53-dependent apoptosis. Nat Cell Biol 2000; 2:730.
  27. Zhong S, Salomoni P, Ronchetti S, et al. Promyelocytic leukemia protein (PML) and Daxx participate in a novel nuclear pathway for apoptosis. J Exp Med 2000; 191:631.
  28. Goddard AD, Borrow J, Freemont PS, Solomon E. Characterization of a zinc finger gene disrupted by the t(15;17) in acute promyelocytic leukemia. Science 1991; 254:1371.
  29. Gallagher RE, Willman CL, Slack JL, et al. Association of PML-RAR alpha fusion mRNA type with pretreatment hematologic characteristics but not treatment outcome in acute promyelocytic leukemia: an intergroup molecular study. Blood 1997; 90:1656.
  30. Slack JL, Willman CL, Andersen JW, et al. Molecular analysis and clinical outcome of adult APL patients with the type V PML-RARalpha isoform: results from intergroup protocol 0129. Blood 2000; 95:398.
  31. González M, Barragán E, Bolufer P, et al. Pretreatment characteristics and clinical outcome of acute promyelocytic leukaemia patients according to the PML-RAR alpha isoforms: a study of the PETHEMA group. Br J Haematol 2001; 114:99.
  32. Perez A, Kastner P, Sethi S, et al. PMLRAR homodimers: distinct DNA binding properties and heteromeric interactions with RXR. EMBO J 1993; 12:3171.
  33. Côté S, Zhou D, Bianchini A, et al. Altered ligand binding and transcriptional regulation by mutations in the PML/RARalpha ligand-binding domain arising in retinoic acid-resistant patients with acute promyelocytic leukemia. Blood 2000; 96:3200.
  34. Grignani F, Ferrucci PF, Testa U, et al. The acute promyelocytic leukemia-specific PML-RAR alpha fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell 1993; 74:423.
  35. Tsai S, Bartelmez S, Heyman R, et al. A mutated retinoic acid receptor-alpha exhibiting dominant-negative activity alters the lineage development of a multipotent hematopoietic cell line. Genes Dev 1992; 6:2258.
  36. Brown D, Kogan S, Lagasse E, et al. A PMLRARalpha transgene initiates murine acute promyelocytic leukemia. Proc Natl Acad Sci U S A 1997; 94:2551.
  37. 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.
  38. Grisolano JL, Wesselschmidt RL, Pelicci PG, Ley TJ. Altered myeloid development and acute leukemia in transgenic mice expressing PML-RAR alpha under control of cathepsin G regulatory sequences. Blood 1997; 89:376.
  39. He LZ, Tribioli C, Rivi R, et al. Acute leukemia with promyelocytic features in PML/RARalpha transgenic mice. Proc Natl Acad Sci U S A 1997; 94:5302.
  40. Early E, Moore MA, Kakizuka A, et al. Transgenic expression of PML/RARalpha impairs myelopoiesis. Proc Natl Acad Sci U S A 1996; 93:7900.
  41. Welch JS, Yuan W, Ley TJ. PML-RARA can increase hematopoietic self-renewal without causing a myeloproliferative disease in mice. J Clin Invest 2011; 121:1636.
  42. Kogan SC, Brown DE, Shultz DB, et al. BCL-2 cooperates with promyelocytic leukemia retinoic acid receptor alpha chimeric protein (PMLRARalpha) to block neutrophil differentiation and initiate acute leukemia. J Exp Med 2001; 193:531.
  43. Le Beau MM, Bitts S, Davis EM, Kogan SC. Recurring chromosomal abnormalities in leukemia in PML-RARA transgenic mice parallel human acute promyelocytic leukemia. Blood 2002; 99:2985.
  44. Slack JL, Yu M. Constitutive expression of the promyelocytic leukemia-associated oncogene PML-RARalpha in TF1 cells: isoform-specific and retinoic acid-dependent effects on growth, bcl-2 expression, and apoptosis. Blood 1998; 91:3347.
  45. Hoemme C, Peerzada A, Behre G, et al. Chromatin modifications induced by PML-RARalpha repress critical targets in leukemogenesis as analyzed by ChIP-Chip. Blood 2008; 111:2887.
  46. Licht JD. Acute promyelocytic leukemia--weapons of mass differentiation. N Engl J Med 2009; 360:928.
  47. Lin RJ, Nagy L, Inoue S, et al. Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature 1998; 391:811.
  48. Grignani F, De Matteis S, Nervi C, et al. Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. Nature 1998; 391:815.
  49. Warrell RP Jr, He LZ, 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.
  50. Bug G, Ritter M, Wassmann B, et al. Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia. Cancer 2005; 104:2717.
  51. Testa U, Grignani F, Samoggia P, et al. The PML/RARalpha fusion protein inhibits tumor necrosis factor-alpha-induced apoptosis in U937 cells and acute promyelocytic leukemia blasts. J Clin Invest 1998; 101:2278.
  52. Minucci S, Monestiroli S, Giavara S, et al. PML-RAR induces promyelocytic leukemias with high efficiency following retroviral gene transfer into purified murine hematopoietic progenitors. Blood 2002; 100:2989.
  53. 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.
  54. Nasr R, Guillemin MC, Ferhi O, et al. Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation. Nat Med 2008; 14:1333.
  55. Chen Z, Brand NJ, Chen A, et al. Fusion between a novel Krüppel-like zinc finger gene and the retinoic acid receptor-alpha locus due to a variant t(11;17) translocation associated with acute promyelocytic leukaemia. EMBO J 1993; 12:1161.
  56. Chen Z, Guidez F, Rousselot P, et al. 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 U S A 1994; 91:1178.
  57. Guidez F, Huang W, Tong JH, et al. Poor response to all-trans retinoic acid therapy in a t(11;17) PLZF/RAR alpha patient. Leukemia 1994; 8:312.
  58. Licht JD, Chomienne C, Goy A, et al. Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17). Blood 1995; 85:1083.
  59. 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.
  60. Wells RA, Hummel JL, De Koven A, et al. A new variant translocation in acute promyelocytic leukaemia: molecular characterization and clinical correlation. Leukemia 1996; 10:735.
  61. 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 alpha in acute promyelocytic-like leukaemia. Hum Mol Genet 1999; 8:1741.
  62. Dong S, Tweardy DJ. Interactions of STAT5b-RARalpha, a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways. Blood 2002; 99:2637.
  63. Collins SJ. Acute promyelocytic leukemia: STATs, HATs, and HDACs. Blood 2002; 99:2635.
  64. Yamamoto Y, Tsuzuki S, Tsuzuki M, et al. BCOR as a novel fusion partner of retinoic acid receptor alpha in a t(X;17)(p11;q12) variant of acute promyelocytic leukemia. Blood 2010; 116:4274.
  65. Lucena-Araujo AR, Kim HT, Jacomo RH, et al. Internal tandem duplication of the FLT3 gene confers poor overall survival in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based chemotherapy: an International Consortium on Acute Promyelocytic Leukemia study. Ann Hematol 2014; 93:2001.
  66. Poiré X, Moser BK, Gallagher RE, et al. Arsenic trioxide in front-line therapy of acute promyelocytic leukemia (C9710): prognostic significance of FLT3 mutations and complex karyotype. Leuk Lymphoma 2014; 55:1523.
  67. Gallagher RE, Moser BK, Racevskis J, et al. Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia. Blood 2012; 120:2098.
  68. Madan V, Shyamsunder P, Han L, et al. Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia. Leukemia 2016; 30:1672.
  69. Li K, Wang F, Cao WB, et al. TRIB3 Promotes APL Progression through Stabilization of the Oncoprotein PML-RARα and Inhibition of p53-Mediated Senescence. Cancer Cell 2017; 31:697.