Acute Promyelocytic Leukemia: A Paradigm for Differentiation Therapy

  • David GrimwadeEmail author
  • Anita R. Mistry
  • Ellen Solomon
  • Fabien Guidez
Part of the Cancer Treatment and Research book series (CTAR, volume 145)


Acute promyelocytic leukemia(APL) is characterized by the t(15;17) chromosomal translocation leading to the formation of the PML-RARα oncoprotein. This leukemia has attracted considerable interest in recent years, being the first in which therapies that specifically target the underlying molecular lesion, i.e., all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), leading to induction of differentiation and apoptosis have been successfully used in clinical practice. The advent of ATRA therapy has transformed APL from being a disease with a poor outlook to one of the most prognostically favorable subsets of acute myeloid leukemia. Further improvements in outcome may be achieved with the use of ATO, which achieves high rates of remission in the relatively small proportion of patients now relapsing following standard first-line therapy with ATRA and anthracycline-based chemotherapy. Moreover, recent studies have suggested that ATO and ATRA, or even ATO alone, used as front-line treatment of PML-RARA- associated APL can induce long-term remissions. This raises the possibility that some patients can be cured using differentiation therapies alone, without the need for chemotherapy, thereby potentially reducing treatment-related toxicity. It is clear that the success of such an approach is critically dependent upon molecular diagnostics and monitoring for minimal residual disease (MRD) to distinguish those patients who can potentially be cured with differentiation therapy from those requiring additional myelosuppressive agents. This represents an exciting new phase in the treatment of acute leukemia, highlighting the potential of molecularly targeted and MRD-directed therapies to achieve an individualized approach to patient management.


Acute Myeloid Leukemia Acute Promyelocytic Leukemia Arsenic Trioxide Gemtuzumab Ozogamicin Acute Promyelocytic Leukemia Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



DG and FG gratefully acknowledge grant support from the Leukaemia Research Fund of Great Britain. DG is also supported by the European LeukemiaNet.


  1. 1.
    Altucci L, Rossin A, Raffelsberger W, Reitmair A, Chomienne C, Gronemeyer H. Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumor-selective death ligand TRAIL. Nat Med. 2001;7:680–686.CrossRefPubMedGoogle Scholar
  2. 2.
    Altucci L, et al. Rexinoid-triggered differentiation and tumor-selective apoptosis of acute myeloid leukemia by protein kinase A-mediated desubordination of retinoid X receptor. Cancer Res. 2005;65:8754–8765.CrossRefPubMedGoogle Scholar
  3. 3.
    Avvisati G, et al. AIDA (all-trans retinoic acid + idarubicin) in newly diagnosed acute promyelocytic leukemia: a Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) pilot study. Blood. 1996;88:1390–1398.PubMedGoogle Scholar
  4. 4.
    Bennett JM, et al. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med. 1985;103:620–625.PubMedGoogle Scholar
  5. 5.
    Benoit G, et al. RAR-independent RXR signaling induces t(15;17) leukemia cell maturation. Embo J. 1999;18:7011–7018.CrossRefPubMedGoogle Scholar
  6. 6.
    Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH. Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the Randomized MRC Trial. Blood. 1999;93:4131–4143.PubMedGoogle Scholar
  7. 7.
    Carbone R, et al. Recruitment of the histone methyltransferase SUV39H1 and its role in the oncogenic properties of the leukemia-associated PML-retinoic acid receptor fusion protein. Mol Cell Biol. 2006;26:1288–1296.CrossRefPubMedGoogle Scholar
  8. 8.
    Castaigne S, et al. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood. 1990;76:1704–1709.PubMedGoogle Scholar
  9. 9.
    Catalano A, et al. The PRKAR1A gene is fused to RARA in a new variant acute promyelocytic leukemia. Blood. 2007;110:4073–4076.Google Scholar
  10. 10.
    Chambon P. A decade of molecular biology of retinoic acid receptors. Faseb J. 1996;10:940–954.PubMedGoogle Scholar
  11. 11.
    Chou WC, Jie C, Kenedy AA, Jones RJ, Trush MA, Dang CV. Role of NADPH oxidase in arsenic-induced reactive oxygen species formation and cytotoxicity in myeloid leukemia cells. Proc Natl Acad Sci USA. 2004;101:4578–4583.CrossRefPubMedGoogle Scholar
  12. 12.
    Davison K, Mann KK, Waxman S, Miller WH, Jr. JNK activation is a mediator of arsenic trioxide-induced apoptosis in acute promyelocytic leukemia cells. Blood. 2004;103:3496–3502.CrossRefPubMedGoogle Scholar
  13. 13.
    de Thé H, Chomienne C, Lanotte M, Degos L, Dejean A. 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.CrossRefPubMedGoogle Scholar
  14. 14.
    Degos L. The history of acute promyelocytic leukaemia. Br J Haematol. 2003;122:539–553.CrossRefPubMedGoogle Scholar
  15. 15.
    Di Croce L, et al. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science. 2002;295:1079–1082.CrossRefPubMedGoogle Scholar
  16. 16.
    Douer D, Tallman MS. Arsenic trioxide: new clinical experience with an old medication in hematologic malignancies. J Clin Oncol. 2005;23:2396–2410.CrossRefPubMedGoogle Scholar
  17. 17.
    Duprez E, Wagner K, Koch H, Tenen DG. C/EBPbeta: a major PML-RARA-responsive gene in retinoic acid-induced differentiation of APL cells. Embo J. 2003;22:5806–5816.CrossRefPubMedGoogle Scholar
  18. 18.
    Estey E, et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006;107:3469–3473.CrossRefPubMedGoogle Scholar
  19. 19.
    Falanga A, Rickles FR. Pathogenesis and management of the bleeding diathesis in acute promyelocytic leukaemia. Best Pract Res Clin Haematol. 2003;16:463–482.CrossRefPubMedGoogle Scholar
  20. 20.
    Fenaux P, et al. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood. 1999;94:1192–1200.PubMedGoogle Scholar
  21. 21.
    Fenaux P, et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91 Group. Blood. 1993;82:3241–3249.PubMedGoogle Scholar
  22. 22.
    Frankel SR, Eardley A, Lauwers G, Weiss M, Warrell RP, Jr. The “retinoic acid syndrome” in acute promyelocytic leukemia. Ann Intern Med. 1992;117:292–296.PubMedGoogle Scholar
  23. 23.
    Gallagher RE. Retinoic acid resistance in acute promyelocytic leukemia. Leukemia. 2002;16:1940–1958.CrossRefPubMedGoogle Scholar
  24. 24.
    Garcia-Manero G, et al. Phase I/II study of the combination of 5-aza-2′ -deoxycytidine with valproic acid in patients with leukemia. Blood. 2006;108:3271–3279.Google Scholar
  25. 25.
    Ghavamzadeh A, et al. Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy. Ann Oncol. 2006;17:131–134.CrossRefPubMedGoogle Scholar
  26. 26.
    Giafis N, et al. Role of the p38 mitogen-activated protein kinase pathway in the generation of arsenic trioxide-dependent cellular responses. Cancer Res. 2006;66:6763–6771.CrossRefPubMedGoogle Scholar
  27. 27.
    Gore SD, et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res. 2006;66:6361–6369.CrossRefPubMedGoogle Scholar
  28. 28.
    Grignani F, et al. Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. Nature. 1998;391:815–818.CrossRefPubMedGoogle Scholar
  29. 29.
    Grimwade D, et al. Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party. Groupe Francais de Cytogenetique Hematologique, Groupe de Francais d'Hematologie Cellulaire, UK Cancer Cytogenetics Group and BIOMED 1 European Community-Concerted Action “Molecular Cytogenetic Diagnosis in Haematological Malignancies”. Blood. 2000;96:1297–1308.PubMedGoogle Scholar
  30. 30.
    Grimwade D, et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood. 1998;92:2322–2333.PubMedGoogle Scholar
  31. 31.
    Guidez F, Ivins S, Zhu J, Söderström 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.PubMedGoogle Scholar
  32. 32.
    Guillemin MC, et al. In vivo activation of cAMP signaling induces growth arrest and differentiation in acute promyelocytic leukemia. J Exp Med. 2002;196:1373–1380.CrossRefPubMedGoogle Scholar
  33. 33.
    Hayakawa F, Privalsky ML. Phosphorylation of PML by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis. Cancer Cell. 2004;5:389–401.CrossRefPubMedGoogle Scholar
  34. 34.
    He LZ, et al. Distinct interactions of PML-RARalpha and PLZF-RARalpha with co-repressors determine differential responses to RA in APL. Nat Genet. 1998;18:126–135.CrossRefPubMedGoogle Scholar
  35. 35.
    Head D, et al. Effect of aggressive daunomycin therapy on survival in acute promyelocytic leukemia. Blood. 1995;86:1717–1728.PubMedGoogle Scholar
  36. 36.
    Hong SH, Yang Z, Privalsky ML. Arsenic trioxide is a potent inhibitor of the interaction of SMRT corepressor with its transcription factor partners, including the PML-retinoic acid receptor alpha oncoprotein found in human acute promyelocytic leukemia. Mol Cell Biol. 2001;21:7172–7182.CrossRefPubMedGoogle Scholar
  37. 37.
    Huang ME, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood. 1988;72:567–572.PubMedGoogle Scholar
  38. 38.
    Joe Y, et al. ATR, PML, and CHK2 Play a Role in Arsenic Trioxide-induced Apoptosis. J Biol Chem. 2006;281:28764–28771.CrossRefPubMedGoogle Scholar
  39. 39.
    Kamashev D, Vitoux D, de Thé H. PML-RARA-RXR oligomers mediate retinoid and rexinoid/cAMP cross-talk in acute promyelocytic leukemia cell differentiation. J Exp Med. 2004;199:1163–1174.CrossRefPubMedGoogle Scholar
  40. 40.
    Kitamura K, Hoshi S, Koike M, Kiyoi H, Saito H, Naoe T. Histone deacetylase inhibitor but not arsenic trioxide differentiates acute promyelocytic leukaemia cells with t(11;17) in combination with all-trans retinoic acid. Br J Haematol. 2000;108:696–702.CrossRefPubMedGoogle Scholar
  41. 41.
    Kondo T, Mori A, Darmanin S, Hashino S, Tanaka J, Asaka M. The seventh pathogenic fusion gene FIP1L1-RARA was isolated from a t(4;17)-positive acute promyelocytic leukemia. Haematologica. 2008;93:1414–1416.Google Scholar
  42. 42.
    Kurokawa R, et al. Polarity-specific activities of retinoic acid receptors determined by a co-repressor. Nature. 1995;377:451–454.CrossRefPubMedGoogle Scholar
  43. 43.
    Kurokawa R, et al. Regulation of retinoid signalling by receptor polarity and allosteric control of ligand binding. Nature. 1994;371:528–531.CrossRefPubMedGoogle Scholar
  44. 44.
    Kwok C, Zeisig BB, Dong S, So CW. Forced homo-oligomerization of RARalpha leads to transformation of primary hematopoietic cells. Cancer Cell. 2006;9:95–108.CrossRefPubMedGoogle Scholar
  45. 45.
    Larson RS, Brown DC, Sklar LA. Retinoic acid induces aggregation of the acute promyelocytic leukemia cell line NB-4 by utilization of LFA-1 and ICAM-2. Blood. 1997;90:2747–2756.PubMedGoogle Scholar
  46. 46.
    Latagliata R, et al. Therapy-related myelodysplastic syndrome-acute myelogenous leukemia in patients treated for acute promyelocytic leukemia: an emerging problem. Blood. 2002;99:822–824.CrossRefPubMedGoogle Scholar
  47. 47.
    Leoni F, et al. Arsenic trioxide therapy for relapsed acute promyelocytic leukemia: a bridge to transplantation. Haematologica. 2002;87:485–489.PubMedGoogle Scholar
  48. 48.
    Leung J, Pang A, Yuen WH, Kwong YL, Tse EW. Relationship of expression of aquaglyceroporin 9 with arsenic uptake and sensitivity in leukemia cells. Blood. 2007;109:740–746.Google Scholar
  49. 49.
    Lin RJ, Nagy L, Inoue S, Shao W, Miller WH, Evans RM. Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature. 1998;391:811–814.CrossRefPubMedGoogle Scholar
  50. 50.
    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.CrossRefPubMedGoogle Scholar
  51. 51.
    Lobe I, et al. Myelodysplastic syndrome after acute promyelocytic leukemia: the European APL group experience. Leukemia. 2003;17:1600–1604.CrossRefPubMedGoogle Scholar
  52. 52.
    Lu DP, et al. Tetra-arsenic tetra-sulfide for the treatment of acute promyelocytic leukemia: a pilot report. Blood. 2002;99:3136–3143.CrossRefPubMedGoogle Scholar
  53. 53.
    Marasca R, et al. Missense mutations in the PML/RARalpha ligand binding domain in ATRA-resistant As(2)O(3) sensitive relapsed acute promyelocytic leukemia. Haematologica. 1999;84:963–968.PubMedGoogle Scholar
  54. 54.
    Marchetti M, Falanga A, Giovanelli S, Oldani E, Barbui T. All-trans-retinoic acid increases adhesion to endothelium of the human promyelocytic leukaemia cell line NB4. Br J Haematol. 1996;93:360–366.CrossRefPubMedGoogle Scholar
  55. 55.
    Mathews V, et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood. 2006;107:2627–2632.CrossRefPubMedGoogle Scholar
  56. 56.
    McMullin MF, Nugent E, Thompson A, Hull D, Jones FG, Grimwade D. Prolonged molecular remission in PML-RARalpha-positive acute promyelocytic leukemia treated with minimal chemotherapy followed by maintenance including the histone deacetylase inhibitor sodium valproate. Leukemia. 2005;19:1676–1677.CrossRefPubMedGoogle Scholar
  57. 57.
    Milligan DW, et al. Guidelines on the management of acute myeloid leukaemia in adults. Br J Haematol. 2006;135:450–474.Google Scholar
  58. 58.
    Minucci S, et al. Oligomerization of RAR and AML1 transcription factors as a novel mechanism of oncogenic activation. Mol Cell. 2000;5:811–820.CrossRefPubMedGoogle Scholar
  59. 59.
    Mistry AR, Pedersen EW, Solomon E, Grimwade D. The molecular pathogenesis of acute promyelocytic leukaemia: implications for the clinical management of the disease. Blood Rev. 2003;17:71–97.CrossRefPubMedGoogle Scholar
  60. 60.
    Paietta E, et al. Significantly lower P-glycoprotein expression in acute promyelocytic leukemia than in other types of acute myeloid leukemia: immunological, molecular and functional analyses. Leukemia. 1994;8:968–973.PubMedGoogle Scholar
  61. 61.
    Rosenfeld MG, Glass CK. Coregulator codes of transcriptional regulation by nuclear receptors. J Biol Chem. 2001;276:36865–36868.CrossRefPubMedGoogle Scholar
  62. 62.
    Rosenfeld MG, Lunyak VV, Glass CK. Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. Genes Dev. 2006;20:1405–1428.CrossRefPubMedGoogle Scholar
  63. 63.
    Sanz MA, et al. A modified AIDA protocol with anthracycline-based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/RARalpha-positive acute promyelocytic leukemia. PETHEMA group. Blood. 1999;94:3015–3021.PubMedGoogle Scholar
  64. 64.
    Sanz MA, Fenaux P, Lo Coco F. Arsenic trioxide in the treatment of acute promyelocytic leukemia. A review of current evidence. Haematologica. 2005;90:1231–1235.PubMedGoogle Scholar
  65. 65.
    Sanz MA, Tallman MS, Lo-Coco F. Tricks of the trade for the appropriate management of newly diagnosed acute promyelocytic leukemia. Blood. 2005;105:3019–3025.CrossRefPubMedGoogle Scholar
  66. 66.
    Shen ZX, et al. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2004;101:5328–5335.CrossRefPubMedGoogle Scholar
  67. 67.
    Soignet SL, et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med. 1998;339:1341–1348.CrossRefPubMedGoogle Scholar
  68. 68.
    Soignet SL, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19:3852–3860.PubMedGoogle Scholar
  69. 69.
    Sternsdorf T, et al. Forced retinoic acid receptor alpha homodimers prime mice for APL-like leukemia. Cancer Cell. 2006;9:81–94.CrossRefPubMedGoogle Scholar
  70. 70.
    Tallman MS, et al. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med. 1997;337:1021–1028.CrossRefPubMedGoogle Scholar
  71. 71.
    Verma A, et al. Activation of Rac1 and the p38 mitogen-activated protein kinase pathway in response to arsenic trioxide. J Biol Chem. 2002;277:44988–44995.CrossRefPubMedGoogle Scholar
  72. 72.
    Villa R, et al. The methyl-CpG binding protein MBD1 is required for PML-RARalpha function. Proc Natl Acad Sci USA. 2006;103:1400–1405.CrossRefPubMedGoogle Scholar
  73. 73.
    Warrell RP, Jr, He LZ, Richon V, Calleja E, Pandolfi PP. Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Natl Cancer Inst. 1998;90:1621–1625.CrossRefPubMedGoogle Scholar
  74. 74.
    Warrell RP. Retinoid resistance in acute promyelocytic leukemia:new mechanisms, strategies and implications. Blood. 1993;82:2175–2181.Google Scholar
  75. 75.
    Zheng PZ, et al. Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005;102:7653–7658.CrossRefPubMedGoogle Scholar
  76. 76.
    Zhou DC, Kim SH, Ding W, Schultz C, Warrell RP, Gallagher RE. Frequent mutations in the ligand-binding domain of PML-RARalpha after multiple relapses of acute promyelocytic leukemia: analysis for functional relationship to response to all-trans retinoic acid and histone deacetylase inhibitors in vitro and in vivo. Blood. 2002;99:1356–1363.CrossRefPubMedGoogle Scholar
  77. 77.
    Zhou J, Pérès L, Honoré N, Nasr R, Zhu J, de Thé H. Dimerization-induced corepressor binding and relaxed DNA-binding specificity are critical for PML/RARA induced immortalization. Proc Natl Acad Sci USA. 2006;103:9238–9243.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • David Grimwade
    • 1
    Email author
  • Anita R. Mistry
    • 1
  • Ellen Solomon
    • 1
  • Fabien Guidez
    • 1
  1. 1.Department of Medical and Molecular GeneticsKing’s College London School of MedicineLondonUK

Personalised recommendations