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.

  • Review Article
  • Published:

Acute promyelocytic leukaemia: novel insights into the mechanisms of cure

Key Points

  • Promyelocytic leukaemia (PML)–retinoic acid receptor-α (RARα) is a gain-of-function protein that represses RARα and non-RARα target genes and disrupts PML nuclear bodies. This results in immortal proliferation and the inhibition of terminal differentiation.

  • Various clinical regimens combining retinoic acid (RA), arsenic trioxide and anthracyclines now definitively cure up to 90% of patients with acute promyelocytic leukaemia (APL).

  • RA induces APL differentiation and transient remissions. Arsenic trioxide triggers both apoptosis and differentiation and, as a single agent, allows many APL cures. As initially shown in mouse models, their combination definitively cures most patients.

  • Mechanistically, therapy-induced transcriptional activation (or derepression) is responsible for APL cell differentiation, and PML–RARα degradation by RA or arsenic trioxide results in APL eradication.

  • Arsenic trioxide targets PML through oxidation-triggered disulphide bond formation and direct binding. This results in PML and PML–RARα sumoylation, ubiquitylation and proteasome-mediated degradation.

  • Therapy-triggered oncoprotein degradation could be a generally applicable strategy to treat malignancies driven by fusion proteins or overactivation of transcription factors.

Abstract

The fusion oncogene, promyelocytic leukaemia (PML)–retinoic acid receptor-α (RARA), initiates acute promyelocytic leukaemia (APL) through both a block to differentiation and increased self-renewal of leukaemic progenitor cells. The current standard of care is retinoic acid (RA) and chemotherapy, but arsenic trioxide also cures many patients with APL, and an RA plus arsenic trioxide combination cures most patients. This Review discusses the recent evidence that reveals surprising new insights into how RA and arsenic trioxide cure this leukaemia, by targeting PML–RARα for degradation. Drug-triggered oncoprotein degradation may be a strategy that is applicable to many cancers.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: RA- or arsenic trioxide-induced changes in mouse APLs.
Figure 2: The classical model of APL pathogenesis.
Figure 3: PML–RARα functions.
Figure 4: Schematic representation of PML–RARα degradation induced by RA and arsenic trioxide.

Similar content being viewed by others

References

  1. Warrell, R., de Thé, H., Wang, Z. & Degos, L. Acute promyelocytic leukemia. N. Engl. J. Med. 329, 177–189 (1993).

    Article  CAS  PubMed  Google Scholar 

  2. Wang, Z. Y. & Chen, Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood 111, 2505–2515 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Huang, M. et al. Use of all trans retinoic acid in the treatment of acute promyelocytic leukaemia. Blood 72, 567–572 (1988).

    CAS  PubMed  Google Scholar 

  4. Chen, G.-Q. et al. In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia. As2O3 induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML-RARα/PML proteins. Blood 88, 1052–1061 (1996).

    CAS  PubMed  Google Scholar 

  5. Powell, B. L. et al. Arsenic trioxide improves event-free and over-all survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 12 Aug 2010 (doi:10.1182/blood-2010-269621)

  6. Zhang, P., Wang, S. Y. & Xh, H. Arsenic trioxide-treated 72 cases of acute promyelocytic leukemia. Chin. J. Hematol. 17, 58–62 (1996).

    Google Scholar 

  7. Chen, G. Q. et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As2O3 exerts dose-dependent dual effects on APL cells. Blood 89, 3345–3353 (1997). This paper demonstrates the dual apoptotic and partial differentiating effects of arsenic trioxide.

    CAS  PubMed  Google Scholar 

  8. Castaigne, S. et al. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. 1. Clinical results. Blood 76, 1704–1709 (1990).

    CAS  PubMed  Google Scholar 

  9. Fenaux, P., Chastang, C., Chomienne, C. & Degos, L. Tretinoin with chemotherapy in newly diagnosed acute promyelocytic leukaemia. European APL Group. Lancet 343, 1033 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Sun, H. D., Ma, L., Hu, H. X. & Zhang, T. D. Use of Ai-Ling n.1 injection, combined with pattern identification theory of chinese traditional medicine, in the treatment of acute promyelocytic leukemia: report from 32 patients. Chin. J. Integr. Med. 12, 170–171 (1992).

    Google Scholar 

  11. Lo-Coco, F. et al. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults patients younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood 19 July 2010 (doi:10.1182/blood-2010-03-276196).

  12. Sanz, M. A. et al. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood 115, 5137–5146 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Sanz, M. A. et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 113, 1875–1891 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Hu, J. et al. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc. Natl Acad. Sci. USA 106, 3342–3347 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wang, G. et al. An efficient therapeutic approach to patients with acute promyelocytic leukemia using a combination of arsenic trioxide with low-dose all-trans retinoic acid. Hematol. Oncol. 22, 63–71 (2004).

    Article  PubMed  Google Scholar 

  16. Shen, Z. X. 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. USA 101, 5328–5335 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Estey, E. et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood 107, 3469–3473 (2006). References 14–17 demonstrate the potency of the RA–arsenic trioxide combination in patients.

    Article  CAS  PubMed  Google Scholar 

  18. Ravandi, F. et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J. Clin. Oncol. 27, 504–510 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Vickers, M., Jackson, G. & Taylor, P. The incidence of acute promyelocytic leukemia appears constant over most of a human lifespan, implying only one rate limiting mutation. Leukemia 14, 722–726 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. de Thé, H. et al. The PML-RARα fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell 66, 675–684 (1991).

    Article  PubMed  Google Scholar 

  21. Kakizuka, A. et al. Chromosomal translocation t(15; 17) in human acute promyelocytic leukemia fuses RAR α with a novel putative transcription factor, PML. Cell 66, 663–674 (1991).

    Article  CAS  PubMed  Google Scholar 

  22. Borrow, J., Goddart, A., Sheer, D. & Solomon, E. Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17. Science 249, 1577–1580 (1990).

    Article  CAS  PubMed  Google Scholar 

  23. de Thé, H., Chomienne, C., Lanotte, M., Degos, L. & Dejean, A. The t(15;17) translocation of acute promyelocytic leukemia fuses the retinoic acid receptor a gene to a novel transcribed locus. Nature 347, 558–561 (1990).

    Article  PubMed  Google Scholar 

  24. Akagi, T. et al. Hidden abnormalities and novel classification of t(15;17) acute promyelocytic leukemia (APL) based on genomic alterations. Blood 113, 1741–1748 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chan, I. T. et al. Oncogenic K-ras cooperates with PML-RAR α to induce an acute promyelocytic leukemia-like disease. Blood 108, 1708–1715 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chapiro, E. et al. Expression of T-lineage-affiliated transcripts and TCR rearrangements in acute promyelocytic leukemia: implications for the cellular target of t(15;17). Blood 108, 3484–3493 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Faber, J. & Armstrong, S. A. Mixed lineage leukemia translocations and a leukemia stem cell program. Cancer Res. 67, 8425–8428 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Degos, L. et al. All-trans retinoic acid as a differentiating agent in the treatment of acute promyelocytic leukemia. Blood 85, 2643–2653 (1995).

    CAS  PubMed  Google Scholar 

  29. Tsimberidou, A. M. et al. Single-agent liposomal all-trans retinoic acid can cure some patients with untreated acute promyelocytic leukemia: an update of The University of Texas M. D. Anderson Cancer Center Series. Leuk. Lymphoma 47, 1062–1068 (2006). This paper demonstrates the curative effect of high-dose RA therapy through liposomal administration.

    Article  CAS  PubMed  Google Scholar 

  30. Hu, J. et al. Long-term survival and prognostic study in acute promyelocytic leukemia treated with all-trans-retinoic acid, chemotherapy, and As2O3: an experience of 120 patients at a single institution. Int. J. Hematol. 70, 248–260 (1999).

    CAS  PubMed  Google Scholar 

  31. Guillemin, M. C. et al. In vivo activation of cAMP signaling induces growth arrest and differentiation in acute promyelocytic leukemia. J. Exp. Med. 196, 1373–1380 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Muto, A. et al. A novel differentiation-inducing therapy for acute promyelocytic leukemia with a combination of arsenic trioxide and GM-CSF. Leukemia 15, 1176–1184 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Zhu, Q. et al. Synergic effects of arsenic trioxide and cAMP during acute promyelocytic leukemia cell maturation subtends a novel signaling cross- talk. Blood 99, 1014–1022 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Lallemand-Breitenbach, V. et al. Retinoic acid and arsenic synergize to eradicate leukemic cells in a mouse model of acute promyelocytic leukemia. J. Exp. Med. 189, 1043–1052 (1999). This paper demonstrates a dramatic RA–arsenic trioxide synergy in mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Camacho, L. H. et al. Leukocytosis and the retinoic acid syndrome in patients with acute promyelocytic leukemia treated with arsenic trioxide. J. Clin. Oncol. 18, 2620–2625 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Mathews, V. et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood 107, 2627–2632 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Ghavamzadeh, A. et al. Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy. Ann. Oncol. 17, 131–134 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Mathews, V. et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J. Clin. Oncol. 28, 3866–3871 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Bernardi, R. & Pandolfi, P. P. Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies. Nature Rev. Mol. Cell. Biol. 8, 1006–1016 (2007).

    Article  CAS  Google Scholar 

  40. Lallemand-Breitenbach, V. & de Thé, H. PML nuclear bodies. Cold Spring Harb. Perspect. Biol. 21 April 2010 (doi:10.1101/cshperspect.a000661).

  41. Melnick, A. & Licht, J. D. Deconstructing a disease: RARα, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93, 3167–3215 (1999).

    CAS  PubMed  Google Scholar 

  42. Lin, R. & Evans, R. Acquisition of oncogenic potential by RAR chimeras in acute promyelocytic leukemia through formation of homodimers. Mol. Cell 5, 821–830 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Minucci, S. et al. Oligomerization of RAR and AML1 transcription factors as a novel mechanism of oncogenic activation. Mol. Cell 5, 811–820 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Di Croce, L. et al. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295, 1079–1082 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Kastner, P. et al. Positive and negative regulation of granulopoiesis by endogenous RARα. Blood 97, 1314–1320 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Licht, J. D. Reconstructing a disease: what essential features of the retinoic acid receptor fusion oncoproteins generate acute promyelocytic leukemia? Cancer Cell 9, 73–74 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Kogan, S. C., Hong, S. H., Shultz, D. B., Privalsky, M. L. & Bishop, J. M. Leukemia initiated by PMLRARα: the PML domain plays a critical role while retinoic acid-mediated transactivation is dispensable. Blood 95, 1541–1550 (2000).

    CAS  PubMed  Google Scholar 

  48. Matsushita, H. et al. In vivo analysis of the role of aberrant histone deacetylase recruitment and RAR α blockade in the pathogenesis of acute promyelocytic leukemia. J. Exp. Med. 203, 821–828 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sternsdorf, T. et al. Forced retinoic acid receptor a homodimer prime mice for APL-like leukemia. Cancer Cell 9, 81–94 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Viale, A. et al. Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells. Nature 457, 51–56 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Casini, T. & Pelicci, P.-G. A function of p21 during promyelocytic leukemia cell differentiation independent of CDK inhibition and cell cycle arrest. Oncogene 18, 3235–3243 (1999).

    Article  CAS  PubMed  Google Scholar 

  52. Zhu, J. et al. RXR is an essential component of the oncogenic PML/RARA complex in vivo. Cancer Cell 12, 23–35 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Kamashev, D. E., Vitoux, D. & de Thé, H. PML/RARA-RXR oligomers mediate retinoid- and rexinoid- /cAMP in APL cell differentiation. J. Exp. Med. 199, 1–13 (2004).

    Article  CAS  Google Scholar 

  54. Zeisig, B. B. et al. Recruitment of RXR by homotetrameric RARα fusion proteins is essential for transformation. Cancer Cell 12, 36–51 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Tabe, Y. et al. PML-RARα and AML1-ETO translocations are rarely associated with methylation of the RARβ2 promoter. Ann. Hematol. 85, 689–704 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Martens, J. H. et al. PML-RARα/RXR alters the epigenetic landscape in acute promyelocytic leukemia. Cancer Cell 17, 173–185 (2010). This paper determines PML–RARα DNA binding sites in human APL.

    Article  CAS  PubMed  Google Scholar 

  57. Insinga, A. et al. Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway. Nature Med. 11, 71–76 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Nebbioso, A. et al. Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nature Med. 11, 77–84 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Puccetti, E. et al. AML-associated translocation products block vitamin D3-induced differentiation by sequestering the vitamin D3 receptor. Cancer Res. 62, 7050–7058 (2002).

    CAS  PubMed  Google Scholar 

  60. Purton, L. E. et al. RARγ is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation. J. Exp. Med. 203, 1283–1293 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Taschner, S. et al. Downregulation of RXRα expression is essential for neutrophil development from granulocyte/monocyte progenitors. Blood 109, 971–979 (2006).

    Article  PubMed  Google Scholar 

  62. Wang, K. et al. PML/RARα targets promoter regions containing PU.1 consensus and RARE half sites in acute promyelocytic leukemia. Cancer Cell 17, 186–197 (2010).

    Article  CAS  PubMed  Google Scholar 

  63. Zhu, J. et al. A sumoylation site in PML/RARA is essential for leukemic transformation. Cancer Cell 7, 143–153 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Nasr, R. et al. Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation. Nature Med. 14, 1333–1342 (2008). This paper describes genetic and pharmacological uncoupling of differentiation and leukaemia eradication in mouse APL.

    Article  CAS  PubMed  Google Scholar 

  65. Stielow, B. et al. Identification of SUMO-dependent chromatin-associated transcriptional repression components by a genome-wide RNAi screen. Mol. Cell 29, 742–754 (2008).

    Article  CAS  PubMed  Google Scholar 

  66. Garcia-Dominguez, M. & Reyes, J. C. SUMO association with repressor complexes, emerging routes for transcriptional control. Biochim. Biophys. Acta 1789, 451–459 (2009).

    Article  CAS  PubMed  Google Scholar 

  67. Salomoni, P. & Khelifi, A. F. Daxx: death or survival protein? Trends Cell Biol. 16, 97–104 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Torii, S., Egan, D. A., Evans, R. A. & Reed, J. C. Human Daxx regulates Fas-induced apoptosis from nuclear PML oncogenic domains (PODs). EMBO J. 18, 6037–6049 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Drane, P., Ouararhni, K., Depaux, A., Shuaib, M. & Hamiche, A. The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3. Genes Dev. 24, 1253–1265 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Gaillard, E. et al. Phosphorylation by PKA potentiates retinoic acid receptor α activity by means of increasing interaction with and phosphorylation by cyclin H/cdk7. Proc. Natl Acad. Sci. USA 103, 9548–9553 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Rochette-Egly, C., Adam, S., Rossignol, M., Egly, J.-M. & Chambon, P. Stimulation of RARα activation function AF-1 through binding to the general transcription factor TFIIH and phosphorylation by CDK7. Cell 90, 97–107 (1997).

    Article  CAS  PubMed  Google Scholar 

  72. Bruck, N. et al. A coordinated phosphorylation cascade initiated by p38MAPK/MSK1 directs RARα to target promoters. EMBO J. 28, 34–47 (2009).

    Article  CAS  PubMed  Google Scholar 

  73. Glasow, A., Prodromou, N., Xu, K., von Lindern, M. & Zelent, A. Retinoids and myelomonocytic growth factors cooperatively activate RARA and induce human myeloid leukemia cell differentiation via MAP kinase pathways. Blood 105, 341–349 (2005).

    Article  CAS  PubMed  Google Scholar 

  74. Villa, R. et al. Role of the polycomb repressive complex 2 in acute promyelocytic leukemia. Cancer Cell 11, 513–525 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Boukarabila, H. et al. The PRC1 Polycomb group complex interacts with PLZF/RARA to mediate leukemic transformation. Genes Dev. 23, 1195–1206 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Pietersen, A. M. & van Lohuizen, M. Stem cell regulation by polycomb repressors: postponing commitment. Curr. Opin. Cell Biol. 20, 201–207 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Du, C., Redner, R. L., Cooke, M. P. & Lavau, C. Overexpression of wild-type retinoic acid receptor α (RARα) recapitulates retinoic acid-sensitive transformation of primary myeloid progenitors by acute promyelocytic leukemia RAR α-fusion genes. Blood 94, 793–802 (1999).

    CAS  PubMed  Google Scholar 

  78. Salomoni, P. & Pandolfi, P. P. The role of PML in tumor suppression. Cell 108, 165–170 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Bernardi, R., Papa, A. & Pandolfi, P. P. Regulation of apoptosis by PML and the PML-NBs. Oncogene 27, 6299–6312 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Takahashi, Y., Lallemand-Breitenbach, V., Zhu, J. & de Thé, H. PML nuclear bodies and apoptosis. Oncogene 23, 2819–2824 (2004).

    Article  CAS  PubMed  Google Scholar 

  81. Ito, K. et al. PML targeting eradicates quiescent leukaemia-initiating cells. Nature 453, 1072–1078 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Regad, T., Bellodi, C., Nicotera, P. & Salomoni, P. The tumor suppressor PML regulates cell fate in the developing neocortex. Nature Neurosci. 12, 132–140 (2009).

    Article  CAS  PubMed  Google Scholar 

  83. Li, W. et al. PML depletion disrupts normal mammary gland development and skews the composition of the mammary luminal cell progenitor pool. Proc. Natl Acad. Sci. USA 106, 4725–4730 (2009). References 81–83 implicate PML in stem cell self-renewal.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Zhong, S., Salomoni, P. & Pandolfi, P. P. The transcriptional role of PML and the nuclear body. Nature Cell Biol. 2, e85–e90 (2000).

    Article  CAS  PubMed  Google Scholar 

  85. Cicalese, A. et al. The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell 138, 1083–1095 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Daniel, M.-T. et al. PML protein expression in hematopoietic and acute promyelocytic leukemia cells. Blood 82, 1858–1867 (1993).

    CAS  PubMed  Google Scholar 

  87. Koken, M. H. M. et al. The t(15;17) translocation alters a nuclear body in a RA-reversible fashion. EMBO J. 13, 1073–1083 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Weis, K. et al. Retinoic acid regulates aberrant nuclear localization of PML/RARa in acute promyelocytic leukemia cells. Cell 76, 345–356 (1994).

    Article  CAS  PubMed  Google Scholar 

  89. Dyck, J. A. et al. A novel macromolecular structure is a target of the promyelocyte- retinoic acid receptor oncoprotein. Cell 76, 333–343 (1994).

    Article  CAS  PubMed  Google Scholar 

  90. Insinga, A. et al. Impairment of p53 acetylation, stability and function by an oncogenic transcription factor. EMBO J. 23, 1144–1154 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Pearson, M. et al. PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 406, 207–210 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. Trotman, L. C. et al. Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441, 523–527 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Song, M. S. et al. The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network. Nature 455, 813–817 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Zhu, J. et al. Arsenic-induced PML targeting onto nuclear bodies: implications for the treatment of acute promyelocytic leukemia. Proc. Natl Acad. Sci. USA 94, 3978–3983 (1997). This paper demonstrates arsenic trioxide-induced PML and PML-RARα degradation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Zhu, J. et al. Retinoic acid induces proteasome-dependent degradation of retinoic acid receptor α (RARα) and oncogenic RARα fusion proteins. Proc. Natl Acad. Sci. USA 96, 14807–14812 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Zhu, J., Lallemand-Breitenbach, V. & de Thé, H. Pathways of retinoic acid- or arsenic trioxide-induced PML/RARα catabolism, role of oncogene degradation in disease remission. Oncogene 20, 7257–7265 (2001).

    Article  CAS  PubMed  Google Scholar 

  97. Quignon, F., Chen, Z. & de Thé, H. Retinoic acid and arsenic: towards oncogene targeted treatments of acute promyelocytic leukaemia. Biochim. Biophys. Acta 1333, M53–M61 (1997).

    CAS  PubMed  Google Scholar 

  98. Nasr, R., Lallemand-Breitenbach, V., Zhu, J., Guillemin, M. C. & de Thé, H. Therapy-induced PML/RARA proteolysis and acute promyelocytic leukemia cure. Clin. Cancer Res. 15, 6321–6326 (2009).

    Article  CAS  PubMed  Google Scholar 

  99. Kogan, S. C. Curing APL: differentiation or destruction? Cancer Cell 15, 7–8 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Licht, J. D. Acute promyelocytic leukemia-weapons of mass differentiation. N. Engl. J. Med. 360, 928–930 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Raelson, J. V. et al. The PML/RARα oncoprotein is a direct molecular target of retinoic acid in acute promyelocytic leukemia cells. Blood 88, 2826–2832 (1996).

    CAS  PubMed  Google Scholar 

  102. Nervi, C. et al. Caspases mediate retinoic acid-induced degradation of the acute promyelocytic leukemia PML/RARα fusion protein. Blood 92, 2244–2251 (1998).

    CAS  PubMed  Google Scholar 

  103. Lane, A. A. & Ley, T. J. Neutrophil elastase cleaves PML-RARα and is important for the development of acute promyelocytic leukemia in mice. Cell 115, 305–318 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Uy, G. L. et al. A protease-resistant PML-RARα has increased leukemogenic potential in a murine model of acute promyelocytic leukemia. Blood 20 July 2010 (doi:10.1182/blood-2008-11-189282).

  105. vom Baur, E. et al. Differential ligand-dependent interactions between the AF-2 activating domain of nuclear receptors and the putative transcriptional intermediary factors mSUG1 and TIF1. EMBO J. 15, 110–124 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Isakson, P., Bjoras, M., Boe, S. O. & Simonsen, A. Autophagy contributes to therapy-induced degradation of the PML/RARA oncoprotein. Blood 23 June 2010 (doi:10.1182/blood-2010-01-261040).

  107. Gu, Z. M. et al. Pharicin B stabilizes retinoic acid receptor-α and presents synergistic differentiation induction with ATRA in myeloid leukemic cells. Blood 25 Aug 2010 (doi:10.1182/blood-2010-02-267963).

  108. Muller, S., Matunis, M. J. & Dejean, A. Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus. EMBO J. 17, 61–70 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Lallemand-Breitenbach, V. et al. Role of promyelocytic leukemia (PML) sumolation in nuclear body formation, 11s proteasome recruitment, and As2O3-induced PML or PML/retinoic acid receptor α degradation. J. Exp. Med. 193, 1361–1372 (2001). This paper demonstrates SUMO-initiated PML proteolysis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Jeanne, M. et al. PML-RARA oxidation and arsenic-binding initiate the antileukemia response of As2O3 . Cancer Cell 18, 88–98 (2010). This paper demonstrates ROS-mediated PML–RARα dimer formation and sumoylation.

    Article  CAS  PubMed  Google Scholar 

  111. Kawata, K., Yokoo, H., Shimazaki, R. & Okabe, S. Classification of heavy-metal toxicity by human DNA microarray analysis. Environ. Sci. Technol. 41, 3769–3774 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Zhang, X. W. et al. Arsenic trioxide controls the fate of the PML-RARα oncoprotein by directly binding PML. Science 328, 240–243 (2010). This paper demonstrates direct arsenic trioxide-binding by PML.

    Article  CAS  PubMed  Google Scholar 

  113. Shen, T. H., Lin, H. K., Scaglioni, P. P., Yung, T. M. & Pandolfi, P. P. The mechanisms of PML-nuclear body formation. Mol. Cell 24, 331–339 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Nacerddine, K. et al. The SUMO pathway is essential for nuclear integrity and chromosome segregation in mice. Dev. Cell 9, 769–779 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Lallemand-Breitenbach, V. et al. Arsenic degrades PML or PML-RARα through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nature Cell Biol. 10, 547–555 (2008).

    Article  CAS  PubMed  Google Scholar 

  116. Tatham, M. H. et al. RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nature Cell Biol. 10, 538–546 (2008). References 115 and 116 demonstrate that PML sumoylation triggers PML ubiquitylation.

    Article  CAS  PubMed  Google Scholar 

  117. Duprez, E., Lillehaug, J. R., Naoe, T. & Lanotte, M. cAMP signalling is decisive for recovery of nuclear bodies (PODs) during maturation of RA-resistant t(15;17) promyelocytic leukemia NB4 cells expressing PML-RARα. Oncogene 12, 2451–2459 (1996).

    CAS  PubMed  Google Scholar 

  118. Benoit, G. et al. RAR-independent RXR signaling induces t(15;17) leukemia cell maturation. EMBO J. 18, 7011–7018 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Altucci, L. et al. Rexinoid-triggered differentiation and tumours selective apoptosis of AML by protein kinase-A-mediated de-subordination of RXR. Cancer Res. 65, 8754–8765 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Lallemand-Breitenbach, V., Zhu, J., Kogan, S., Chen, Z. & de Thé, H. Opinion: how patients have benefited from mouse models of acute promyelocytic leukaemia. Nature Rev. Cancer 5, 821–827 (2005).

    Article  CAS  Google Scholar 

  121. He, L. et al. Two critical hits for promyelocytic leukemia. Mol. Cell 6, 1131–1141 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Wojiski, S. et al. PML-RARα initiates leukemia by conferring properties of self-renewal to committed promyelocytic progenitors. Leukemia 23, 1462–1471 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Guibal, F. C. et al. Identification of a myeloid committed progenitor as the cancer-initiating cell in acute promyelocytic leukemia. Blood 114, 5415–5425 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Zhu, J., Chen, Z., Lallemand-Breitenbach, V. & de Thé, H. How acute promyelocytic leukemia revived arsenic. Nature Rev. Cancer 2, 705–713 (2002).

    Article  CAS  Google Scholar 

  125. Zheng, P. Z. et al. Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc. Natl Acad. Sci. USA 102, 7653–7658 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Rego, E. M., He, L. Z., Warrell, R. P. Jr, Wang, Z. G. & Pandolfi, P. P. 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-RARα and PLZF-RARα oncoproteins. Proc. Natl Acad. Sci. USA 97, 10173–10178 (2000). This paper demonstrates, genetically, that arsenic trioxide only targets PML–RARα APL.

  127. Jing, Y. et al. Combined effect of all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia cells in vitro and in vivo. Blood 97, 264–269 (2001).

    Article  CAS  PubMed  Google Scholar 

  128. Muindi, J. et al. Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid “resistance” in patients with acute promyelocytic leukemia. Blood 79, 299–303 (1992).

    CAS  PubMed  Google Scholar 

  129. Freitas, R. A. et al. Apoptosis induction by (+)α-tocopheryl succinate in the absence or presence of all-trans retinoic acid and arsenic trioxide in NB4, NB4–R2 and primary APL cells. Leuk. Res. 33, 958–963 (2009).

    Article  CAS  PubMed  Google Scholar 

  130. Schlenk, R. F. et al. Gene mutations and response to treatment with all-trans retinoic acid in elderly patients with acute myeloid leukemia. Results from the AMLSG Trial AML HD98B. Haematologica 94, 54–60 (2009).

    Article  CAS  PubMed  Google Scholar 

  131. Chen, Z. 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 in acute promyelocytic leukemia. EMBO J. 12, 1161–1167 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Licht, J. D. et al. Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17). Blood 85, 1083–1094 (1995).

    CAS  PubMed  Google Scholar 

  133. Lin, R. J. et al. Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature 391, 811–814 (1998).

    Article  CAS  PubMed  Google Scholar 

  134. Grignani, F. et al. Fusion proteins of the retinoic acid receptor-α recruit histone deacetylase in promyelocytic leukaemia. Nature 391, 815–818 (1998).

    Article  CAS  PubMed  Google Scholar 

  135. He, L. Z. et al. Distinct interactions of PML-RARalpha and PLZF-RARalpha with co-repressors determine differential responses to RA in APL. Nature Genet. 18, 126–135 (1998)

    Article  CAS  PubMed  Google Scholar 

  136. Rice, K. L. et al. Comprehensive genomic screens identify a role for PLZF-RARα as a positive regulator of cell proliferation via direct regulation of c-MYC. Blood 114, 5499–5511 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Koken, M. H. M. et al. Retinoic acid, but not arsenic trioxide, degrades the PLZF/RARα fusion protein, without inducing terminal differentiation or apoptosis, in a RA-therapy resistant t(11;17)(q23;q21) APL patient. Oncogene 18, 1113–1118 (1999).

    Article  CAS  PubMed  Google Scholar 

  138. Petti, M. C. et al. Complete remission through blast cell differentiation in PLZF/RARα-positive acute promyelocytic leukemia: in vitro and in vivo studies. Blood 100, 1065–1067 (2002).

    Article  CAS  PubMed  Google Scholar 

  139. Guidez, F. et al. RARα-PLZF overcomes PLZF-mediated repression of CRABPI, contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia. Proc. Natl Acad. Sci. USA 104, 18694–18699 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Tallman, M. S. & Altman, J. K. How I treat acute promyelocytic leukemia. Blood 114, 5126–5135 (2009).

    Article  CAS  PubMed  Google Scholar 

  141. Cyranoski, D. Arsenic patent keeps drug for rare cancer out of reach of many. Nature Med. 13, 1005 (2007).

    Article  CAS  PubMed  Google Scholar 

  142. Kastner, P. & Chan, S. Function of RARα during the maturation of neutrophils. Oncogene 20, 7178–7185 (2001).

    Article  CAS  PubMed  Google Scholar 

  143. Wang, Z.-G. et al. PML is essential for multiple apoptotic pathways. Nature Genet. 20, 266–272 (1998).

    Article  CAS  PubMed  Google Scholar 

  144. Zhang, Q. Y. et al. A systems biology understanding of the synergistic effects of arsenic sulfide and Imatinib in BCR/ABL-associated leukemia. Proc. Natl Acad. Sci. USA 106, 3378–3383 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. El-Sabban, M. E. et al. Arsenic-interferon-α-triggered apoptosis in HTLV-I transformed cells is associated with tax down-regulation and reversal of NF-κB activation. Blood 96, 2849–2855 (2000).

    CAS  PubMed  Google Scholar 

  146. Kchour, G. et al. Phase 2 study of the efficacy and safety of the combination of arsenic trioxide, interferon α, and zidovudine in newly diagnosed chronic adult T-cell leukemia/lymphoma (ATL). Blood 113, 6528–6532 (2009).

    Article  CAS  PubMed  Google Scholar 

  147. Wu, X. et al. The tamoxifen metabolite, endoxifen, is a potent antiestrogen that targets estrogen receptor α for degradation in breast cancer cells. Cancer Res. 69, 1722–1727 (2009).

    Article  CAS  PubMed  Google Scholar 

  148. Douer, D. et al. Acute promyelocytic leukaemia in patients originating in Latin America is associated with an increased frequency of the bcr1 subtype of the PML/RARα fusion gene. Br. J. Haematol. 122, 563–570 (2003).

    Article  CAS  PubMed  Google Scholar 

  149. Zhang, Z. R. et al. Using sound Clinical Paths and Diagnosis-related Groups (DRGs)-based payment reform to bring benefits to patient care: a case study of leukemia therapy. Front. Med. China 4, 8–15 (2010).

    Article  CAS  Google Scholar 

  150. Strickland, S. & Mahdavi, V. The induction of differentiation in teratocarcinoma stem cells by retinoic acid. Cell 15, 393–403 (1978).

    Article  CAS  PubMed  Google Scholar 

  151. Sidell, N. Retinoic acid-induced growth inhibition and morphologic differentiation of human neuroblastoma cells in vitro. J. Natl Cancer Inst. 68, 589–596 (1982).

    CAS  PubMed  Google Scholar 

  152. Breitman, T. R., Collins, S. J. & Keene, B. R. Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acid. Blood 57, 1000–1004 (1981).

    CAS  PubMed  Google Scholar 

  153. Chomienne, C. et al. All-trans retinoic acid in acute promyelocytic leukemias. II. In vitro studies: structure-function relationship. Blood 76, 1710–1717 (1990).

    CAS  PubMed  Google Scholar 

  154. Wang, J. C. & Dick, J. E. Cancer stem cells: lessons from leukemia. Trends Cell Biol. 15, 494–501 (2005).

    Article  CAS  PubMed  Google Scholar 

  155. Zhang, S.-Y. et al. Establishment of a human acute promyelocytic leukemia-ascites model in SCID mice. Blood 87, 3404–3409 (1996).

    CAS  PubMed  Google Scholar 

  156. Brown, D. et al. A PML RARα transgene initiates murine acute promyelocytic leukemia. Proc. Natl Acad. Sci. USA 94, 2551–2556 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. He, L.-Z. et al. Acute leukemia with promyelocytic features in PML/RARα transgenic mice. Proc. Natl Acad. Sci. USA 94, 5302–5307 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Grisolano, J. L., Wesselschmidt, R. L., Pelicci, P. G. & Ley, T. J. Altered myeloid development and acute leukemia in transgenic mice expressing PML-RARα under control of cathepsin G regulatory sequences. Blood 89, 376–387 (1997).

    CAS  PubMed  Google Scholar 

  159. Westervelt, P. et al. High-penetrance mouse model of acute promyelocytic leukemia with very low levels of PML-RARα expression. Blood 102, 1857–1865 (2003).

    Article  CAS  PubMed  Google Scholar 

  160. Welch, J. S., Yuan, W. & Ley, T. J. Expression of PML-RARα by the murine PML locus leads to myeloid self-renewal, clonal expansion and morphologic promyelocytic leukemia. Blood (ASH Anual Meeting Abstracts) 112, Abstract 932 (2008).

    Article  Google Scholar 

Download references

Acknowledgements

The authors would like to apologize to their many friends and colleagues whose work could not be cited because of space restrictions. Work in our laboratories is supported by the Ligue Nationale contre le Cancer, France; Institut Universitaire de France, France; Institut National du Cancer, France; the EPITRON FP6 NOE of the European Economic community, National High Tech Program for Biotechnology of China, the Chinese National Key Basic Research Project, China; the National Natural Science Foundation of China, the Key Discipline Program of Shanghai Municipal Education Commission, China. We thank J. Zhu, V. Lallemand-Breitenbach and J. Ablain for their critical reading of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Hugues de Thé.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

National Cancer Institute Drug Dictionary 

arsenic trioxide

imatinib

retinoic acid

Pathway Interaction Database 

p53 signalling

PML

RARα

FURTHER INFORMATION

Hugues de Thé's homepage

Hugues de Thé and Zhu Chen's homepage

Shanghai Institute of Haematology

Glossary

Differentiation syndrome

A complication of treatment with RA or arsenic trioxide in patients with PML–RARα APL in which differentiating leukaemic myeloid cells secrete cytokines that induce capillary leaks and pulmonary distress.

Transcription factor IIH

TFIIH. A protein complex associated with RNA polymerase II. It is implicated in both transcription-coupled DNA repair and transcriptional regulation.

Polycomb group

First identified in the Drosophila melanogaster, the two polycomb group repressive complexes maintain the silencing of several key genes involved in differentiation (including the Hox clusters) through chromatin modifications, which favours a stem cell-like phenotype. Enhanced expression of polycomb group genes has been repeatedly associated with cancer.

PML nuclear bodies

Protein-containing domains organized by PML that are regulated by ROS and recruit various proteins, resulting in their sequestration or post-translational modification.

Phosphodiesterase

A large class of enzymes that degrade cAMP or cGMP; inhibitors of the different phosphodiesterases stimulate cAMP or cGMP signalling.

Rights and permissions

Reprints and permissions

About this article

Cite this article

de Thé, H., Chen, Z. Acute promyelocytic leukaemia: novel insights into the mechanisms of cure. Nat Rev Cancer 10, 775–783 (2010). https://doi.org/10.1038/nrc2943

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2943

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing