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.

  • Timeline
  • Published:

How acute promyelocytic leukaemia revived arsenic

Nature Reviews Cancer volume 2, pages 705–714 (2002)Cite this article

Key Points

  • Arsenicals are some of the oldest drugs known to man. For more than 2,000 years, physicians have progressively switched from natural sulphur derivatives, to white arsenic, from ointments to oral forms, culminating in the massive use of organic arsenicals against syphilis in the 1900s.

  • In the 1990s, Chinese scientists revived arsenic trioxide therapy by showing that it induces marked responses in patients with acute promyelocytic leukaemia (APL). Such exquisite sensitivity of APL to arsenic is likely to relate to its effects on the PML gene product, which is fused to the retinoic-acid receptor during the APL-specific t(15;17) translocation.

  • The ability of arsenic to treat APL has shed new light on the pathogenesis of this disease, emphasizing the role of transcriptional derepression. APL, which is also exquisitely sensitive to retinoic-acid-induced differentiation, has become a model for both differentiation therapy and oncogene-targeted treatments.

  • Continuing studies are trying to broaden the use of arsenic in cancer therapies.

Abstract

Despite its many therapeutic qualities, arsenic trioxide has been more commonly remembered as Madame Bovary's poison than as an anticancer drug. The ability of arsenic trioxide to treat acute promyelocytic leukaemia has radically changed this view, providing new insights into the pathogenesis of this malignancy and raising hopes that arsenicals might be useful in treating other cancers.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Two effects of retinoic acid and As2O3 on PML–RARα function.
Figure 2: Model for the effect of retinoic-acid receptor (RAR) and PML–RARα on myeloid differentiation.
Figure 3: Effects of retinoic acid (RA) and As2O3 on acute promyelocytic leukaemia in vivo.

References

  1. Micca, G. Arsenic, or rather, arsenious anhydride, the preferred poison of the Borgias. Minerva Med. 60, IX–XI (1969).

    CAS  PubMed  Google Scholar 

  2. Keynes, M. Did Napoleon die from arsenical poisoning? Lancet 344, 276 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Alpert, M. A touch of poison. Sci. Am. 284, 20–21 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Huff, J., Chan, P. & Nyska, A. Is the human carcinogen arsenic carcinogenic to laboratory animals? Toxicol. Sci. 55, 17–23 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Bode, A. M. & Dong, Z. The paradox of arsenic: molecular mechanisms of cell transformation and chemotherapeutic effects. Crit. Rev. Oncol. Hematol. 42, 5–24 (2002).

    Article  PubMed  Google Scholar 

  6. Haller, J. S. Therapeutic mule: the use of arsenic in the nineteenth century materia medica. Pharm. Hist. 17, 87–100 (1975).

  7. Kwong, Y. L. & Todd, D. Delicious poison: arsenic trioxide for the treatment of leukemia. Blood 89, 3487–3488 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Waxman, S. & Anderson, K. C. History of the development of arsenic derivatives in cancer therapy. Oncologist 6, 3–10 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Sun, H. D. et al. Ai-ling 1 treated 32 cases of acute promyelocytic leukemia. Chin. J. Integrat. Trad. Chin. West. Med. 12, 170–171 (1992).First report of As 2 O 3 therapy in APL.

  10. Zhang, P. et al. Treatment of 72 cases of acute promyelocytic leukemia with intravenous arsenic trioxide. Chin. J. Hematol. 17, 58–62 (1996).

    Google Scholar 

  11. 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-RAR α/PML proteins. Blood 88, 1052–1061 (1996).

    Article  CAS  PubMed  Google Scholar 

  12. Chen, G.-Q. et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukaemia (APL). I. As2O3 exerts dose-dependent dual effects on APL cells. Blood 89, 3345–3353 (1997).First demonstration of differentiation triggered by low doses of As 2 O 3 , specifically in APL cells. Greater doses induce apoptosis, as in various non-APL cell lines.

    Article  CAS  PubMed  Google Scholar 

  13. Espinoza, E., Mann, M. & Bleasdell, B. Arsenic and mercury in traditional chinese herbal balls. N. Engl. J. Med. 333, 803–804 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Soignet, S. L. et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N. Engl. J. Med. 339, 1341–1348 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Lu, D. P. et al. Tetra-arsenic tetra sulfide for the treatment of acute promyelocytic leukemia: a pilot report. Blood 99, 3136–3143 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. 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 

  17. de Thé, H. et al. The t(15;17) translocation of acute promyelocytic leukemia fuses the retinoic acid receptor-α gene to a novel transcribed locus. Nature 347, 558–561 (1990).

    Article  PubMed  Google Scholar 

  18. 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 

  19. Huang, M. et al. Use of all trans retinoic acid in the treatment of acute promyelocytic leukaemia. Blood 72, 567–572 (1988).First demonstration that retinoic acid induces the differentiation of acute promyelocytic leukaemia cells in vivo , resulting in complete remission in patients with this cancer.

    Article  CAS  PubMed  Google Scholar 

  20. Rochette-Egly, C. et al. 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 

  21. de Thé, H., Marchio, A., Tiollais, P. & Dejean, A. Differential expression and ligand regulation of the retinioc acid receptor α and β genes. EMBO J. 8, 429–433 (1989).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Zhu, J. et al. Lineage restriction of the RARα gene expression in myeloid differentiation. Blood 98, 2563–2567 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Johnson, B. S., Mueller, L., Si, J. & Collins, S. J. The cytokines IL-3 and GM-CSF regulate the transcriptional activity of retinoic acid receptors in different in vitro models of myeloid differentiation. Blood 99, 746–753 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Kastner, P. et al. Positive and negative regulation of granulopoiesis by endogenous RARα. Blood 97, 1314–1320 (2001).Demonstration of an accelerated granulocytic maturation in Rarα−/− mice.

    Article  CAS  PubMed  Google Scholar 

  25. 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 

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

    Article  CAS  PubMed  Google Scholar 

  27. 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 

  28. 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 

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

    Article  CAS  PubMed  Google Scholar 

  30. Hong, S. H. et al. SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor-α (RARα) and PLZF-RARα oncoproteins associated with acute promyelocytic leukemia. Proc. Natl Acad. Sci. USA 94, 9028–9033 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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 

  32. 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 

  33. Chen, Z. et al. Fusion between a novel Kruppel-like zinc finger gene and the retinoic acid receptor-α 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 

  34. Gu, B. W. et al. Variant-type PML-RARα fusion transcript in acute promyelocytic leukemia: use of a cryptic coding sequence from intron 2 of the RARα gene and identification of a new clinical subtype resistant to retinoic acid therapy. Proc. Natl Acad. Sci. USA 99, 7640–7645 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Slack, J. L. et al. Molecular analysis and clinical outcome of adult APL patients with the type V PML–RARα isoform: results from Intergroup protocol 0129. Blood 95, 398–403 (2000).

    CAS  PubMed  Google Scholar 

  36. Perez, A. et al. PML–RAR homodimers: distinct binding properties and heteromeric interactions with RXR. EMBO J. 12, 3171–3182 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jansen, J. H. et al. Multimeric complexes of the PML–retinoic acid receptor-α fusion protein in acute promyelocytic leukemia cells and interference with retinoid and peroxisome-proliferator signaling pathways. Proc. Natl Acad. Sci. USA 92, 7401–7405 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kogan, S. C. et al. BCL-2 cooperates with promyelocytic leukemia retinoic acid receptor-α chimeric protein (PML–RARα) to block neutrophil differentiation and initiate acute leukemia. J. Exp. Med. 193, 531–544 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Le Beau, M. M., Bitts, S., Davis, E. M. & Kogan, S. C. Recurring chromosomal abnormalities in leukemia in PML–RARA transgenic mice parallel human acute promyelocytic leukemia. Blood 99, 2985–2991 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Wang, Z.-G. et al. PML is essential for multiple apoptotic pathways. Nature Genet. 20, 266–272 (1998).Cells devoid of the promyelocytic leukaemia gene product are apoptosis resistant and their myeloid differentiation is impaired.

    Article  CAS  PubMed  Google Scholar 

  41. Wang, Z. G. et al. Role of PML in cell growth and the retinoic acid pathway. Science 279, 1547–1551 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. Quignon, F. et al. PML induces a caspase-independent cell death process. Nature Genet. 20, 259–265 (1998).

    Article  CAS  PubMed  Google Scholar 

  43. Gottifredi, V. & Prives, C. p53 and PML: new partners in tumor suppression. Trends Cell. Biol. 11, 184–187 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Mu, Z. M. et al. PML, a growth suppressor disrupted in acute promyelocytic leukemia. Mol. Cell. Biol. 14, 6858–6867 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Koken, M. H. M. et al. The PML growth-suppressor has an altered expression in human oncogenesis. Oncogene 10, 1315–1324 (1995).

    CAS  PubMed  Google Scholar 

  46. Terris, B. et al. PML nuclear bodies are general targets for inflammation and cell proliferation. Cancer Res. 55, 1590–1597 (1995).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  48. 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 

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

    Article  CAS  PubMed  Google Scholar 

  50. Dyck, J. A. et al. A novel macromolecular structure is a target of the promyelocyte–retinoic acid receptor oncoprotein. Cell 76, 333–343 (1994).References 47–50 were the first to demonstrate the retinoic acid-reversible abnormal localization of the promyelocytic leukaemia gene product in acute promyelocytic leukaemia cells.

    Article  CAS  PubMed  Google Scholar 

  51. Grignani, F. et al. The acute promyelocytic leukemia specific PML/RARα fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell 74, 423–431 (1993).

    Article  CAS  PubMed  Google Scholar 

  52. Yoshida, H. et al. Accelerated degradation of PML–retinoic acid receptor-α (PML-RARα) oncoprotein by all-trans retinoic acid in acute promyelocytic leukemia. Possible role of the proteasome pathway. Cancer Res. 56, 2945–2948 (1996).

    CAS  PubMed  Google Scholar 

  53. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 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).Arsenic degrades PML–RARα by targeting its PML moiety.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 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 

  57. Thomas, D. & Tyers, M. Transcriptional regulation: Kamikaze activators. Curr. Biol. 10, R341–R343 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Altucci, L. et al. Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumor-selective death ligand TRAIL. Nature Med. 7, 680–686 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Liu, T. X. et al. Gene expression networks underlying retinoic acid-induced differentiation of acute promyelocytic leukemia cells. Blood 96, 1496–1504 (2000).

    Article  CAS  PubMed  Google Scholar 

  60. 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 

  61. 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 

  62. Germolec, D. R. et al. Arsenic enhancement of skin neoplasia by chronic stimulation of growth factors. Am. J. Pathol. 153, 1775–1785 (1998).

  63. Kinjo, K. et al. Arsenic trioxide (As2O3)-induced apoptosis and differentiation in retinoic acid-resistant acute promyelocytic leukemia model in hGM-CSF-producing transgenic SCID mice. Leukemia 14, 431–438 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. 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).A mouse model of APL predicts synergy between RA and As 2 O 3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 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 

  66. Lallemand-Breitenbach, V. et al. Role of promyelocytic leukemia (PML) sumoylation 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Shao, W. et al. Arsenic trioxide as an inducer of apoptosis and loss of PML–RARα protein in acute promyelocytic leukemia cells. J. Natl Cancer Inst. 90, 124–133 (1998).

    Article  CAS  PubMed  Google Scholar 

  68. 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 

  69. Zhu, J., Lallemand-Breitenbach, V. & de The, 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 

  70. Hong, S. H., Yang, Z. & Privalsky, M. L. Arsenic trioxide is a potent inhibitor of the interaction of SMRT corepressor with its transcription factor partners, including the PML–retinoic acid receptor-α oncoprotein found in human acute promyelocytic leukemia. Mol. Cell. Biol. 21, 7172–7182 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Rego, E. M. 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–RARα and PLZF–RARα oncoproteins. Proc. Natl Acad. Sci. USA 97, 10173–10178 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 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 

  73. Au, W. Y. et al. Combined arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia recurring from previous relapses successfully treated using arsenic trioxide. Br. J. Haematol. 117, 130–132 (2002).

  74. Koide, T. et al. Active repression of RAR signaling is required for head formation. Genes Dev. 15, 2111–2121 (2001).

  75. Du, C. et al. Overexpression of wild-type retinoic acid receptor-α (RARα) recapitulates retinoic acid-sensitive transformation of primary myeloid progenitors by acute promyelocytic leukemia RARα-fusion genes. Blood 94, 793–802 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Shao, W. et al. A retinoid-resistant acute promyelocytic leukemia subclone expresses a dominant negative PML–RARα mutation. Blood 89, 4282–4289 (1997).

    Article  CAS  PubMed  Google Scholar 

  77. 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).

    Article  CAS  PubMed  Google Scholar 

  78. 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 

  79. Jansen, J. H. et al. Complete remission of t(11;17) positive acute promyelocytic leukemia induced by all-trans retinoic acid and granulocyte colony-stimulating factor. Blood 94, 39–45 (1999).

    Article  CAS  PubMed  Google Scholar 

  80. He, L. Z. et al. Myeloid leukemias in PLZF–RARα transgenic mice. Blood 90, 320a (1997).

    Google Scholar 

  81. Petti, M. 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 

  82. Fogal, V. et al. Regulation of p53 activity in nuclear bodies by a specific PML isoform. EMBO J. 19, 6185–6195 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Guo, A. et al. The function of PML in p53-dependent apoptosis. Nature Cell Biol. 2, 730–736 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Kroemer, G. & de Thé, H. Arsenic trioxide, a novel mitochondriotoxic anti-cancer agent? J. Natl Cancer Inst. 91, 743–745 (1999).

    Article  CAS  PubMed  Google Scholar 

  85. Chou, W. C. et al. Arsenic inhibition of telomerase transcription leads to genetic instability. J. Clin. Invest. 108, 1541–1547 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Bazarbachi, A. et al. Arsenic trioxide and interferon-α synergize to induce cell cycle arrest and apoptosis in HTLV-1 transformed cells. Blood 93, 278–283 (1999).

    Article  CAS  PubMed  Google Scholar 

  87. El-Sabban, M. E. et al. Arsenic–interferon-α-triggered apoptosis in HTLV-1 transformed cells is associated with Tax down-regulation and reversal of NF-κB activation. Blood 96, 2849–2855 (2000).In another leukaemia, acute T-cell leukaemia (ATL), As 2 O 3 combined with interferon-α induces both apoptosis and selective degradation of the Tax retroviral oncogene.

    CAS  PubMed  Google Scholar 

  88. Ishov, A. M. et al. PML is critical for ND10 formation and recruits the PML-interacting protein Daxx to this nuclear structure when modified by SUMO-1. J. Cell Biol. 147, 221–234 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Zhong, S. et al. Role of SUMO-1-modified PML in nuclear body formation. Blood 95, 2748–2752 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  91. Fabunmi, R. P., Wigley, W. C., Thomas, P. J. & DeMartino, G. N. Interferon-γ regulates accumulation of the proteasome activator PA28 and immunoproteasomes at nuclear PML bodies. J. Cell Sci. 114, 29–36 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. Baumann, C. T. et al. The glucocorticoid receptor interacting protein 1 (GRIP1) localizes in discrete nuclear foci that associate with ND10 bodies and are enriched in components of the 26S proteasome. Mol. Endocrinol. 15, 485–500 (2001).

  93. Grobelny, J. V., Godwin, A. K. & Broccoli, D. ALT-associated PML bodies are present in viable cells and are enriched in cells in the G2/M phase of the cell cycle. J. Cell Sci. 113, 4577–4585 (2000).

    Article  CAS  PubMed  Google Scholar 

  94. Lombard, D. B. & Guarente, L. Nijmegen breakage syndrome disease protein and MRE11 at PML nuclear bodies and meiotic telomeres. Cancer Res. 60, 2331–2334 (2000).

    CAS  PubMed  Google Scholar 

  95. Bischof, O. et al. Regulation and localization of the bloom syndrome protein in response to DNA damage. J. Cell Biol. 153, 367–380 (2001).

  96. Wu, G., Lee, W. H. & Chen, P. L. NBS1 and TRF1 colocalize at promyelocytic leukemia bodies during late S/G2 phases in immortalized telomerase-negative cells. Implication of NBS1 in alternative lengthening of telomeres. J. Biol. Chem. 275, 30618–30622 (2000).

    Article  CAS  PubMed  Google Scholar 

  97. Muller, S., Hoege, C., Pyrowolakis, G. & Jentsch, S. SUMO, ubiquitin's mysterious cousin. Nature Rev. Mol. Cell Biol. 2, 202–210 (2001).

  98. Mahajan, R. et al. A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2. Cell 88, 97–107 (1997).

    Article  CAS  PubMed  Google Scholar 

  99. Pichler, A. et al. The nucleoporin RanBP2 has SUMO1 E3 ligase activity. Cell 108, 109–120 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Reymond, A. et al. The tripartite motif family identifies cell compartments. EMBO J. 20, 2140–2151 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Lehembre, F., Muller, S., Pandolfi, P. P. & Dejean, A. Regulation of Pax3 transcriptional activity by SUMO-1-modified PML. Oncogene 20, 1–9 (2001).

    Article  CAS  PubMed  Google Scholar 

  102. 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 

  103. 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 

  104. Merghoub, T., Gurrieri, C., Piazza, F. & Pandolfi, P. P. Modeling acute promyelocytic leukemia in the mouse: new insights in the pathogenesis of human leukemias. Blood Cells Mol. Dis. 27, 231–248 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Kogan, S. C. et al. Leukemia initiated by PML/RARα: the PML domain plays a critical role while retinoic acid-mediated transactivation is dispensable. Blood 95, 1541–1550 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. He, L. Z. et al. Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. J. Clin. Invest. 108, 1321–1330 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Quenech'Du, N. et al. A sustained increase in the endogenous level of cAMP reduces the retinoid concentration required for APL cell maturation to near physiological levels. Leukemia 12, 1829–1833 (1998).

    Article  CAS  PubMed  Google Scholar 

  108. Gianni, M. et al. Phosphorylation by p38MAPK and recruitment of SUG-1 are required for RA-induced RARα degradation and transactivation. EMBO J. 21, 3760–3769 (2002).

  109. Recher, C. et al. In vitro and in vivo effectiveness of arsenic trioxide against murine T- cell prolymphocytic leukaemia. Br. J. Haematol. 117, 343–350 (2002).

  110. Jing, Y., Xia, L. & Waxman, S. Targeted removal of PML-RARα protein is required prior to inhibition of histone deacetylase for overcoming all-trans retinoic acid differentiation resistance in acute promyelocytic leukemia. Blood 100, 1008–1013(2002).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M.T. Daniel for pictures of APL cells, and A. Bazarbachi, L. Degos, H. Dombret and M. Koken for critical reading of the manuscript. We also thank A.M. Pichon for help with the bibliography, L. Marandin for the analysis of DNA arrays and ARECA for supporting the animal facility. J.Z. is supported by the Fondation de France and V.L. by the ARC. The authors' laboratories are supported by the Pôle Sino-Français en Sciences du vivant et en génomique and PRA.

Author information

Authors and Affiliations

  1. CNRS UPR 9051, Laboratoire associé du comité de Paris de la ligue contre le cancer, affilié à l'université de Paris VII, Hôpital St Louis, 1 avenue C. Vellefaux, Paris, cedex 10, 75475, France

    Jun Zhu, Valérie Lallemand-Breitenbach & Hugues de Thé

  2. the State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, Rui-Jin Hospital, Shanghai Second Medical University, 197 Rui-Jin Road II, Shanghai, China

    Jun Zhu & Zhu Chen

Authors
  1. Jun Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Valérie Lallemand-Breitenbach
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hugues de Thé
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hugues de Thé.

Related links

Related links

DATABASES

LocusLink

APO2L

BFL1

CD38

GM-CSF

IFN-α

MCL1

MDM2

NF-κB

PLZF

Pml

PML

RARα

RXR

SMRT

Medscape DrugInfo

imatinib

OMIM

acute promyelocytic leukaemia

acute T-cell leukaemia

bladder cancer

chronic myelogenous leukaemia

chronic lymphocytic leukaemia

lung cancer

multiple myeloma

non-Hodgkin's lymphoma

skin cancer

FURTHER INFORMATION

European Institute of Oncology's acute promyelocytic leukemia site

The Leukemia and Lymphoma Society

Nuclear bodies

PML nuclear bodies (movies)

Retinoic acid

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhu, J., Chen, Z., Lallemand-Breitenbach, V. et al. How acute promyelocytic leukaemia revived arsenic. Nat Rev Cancer 2, 705–714 (2002). https://doi.org/10.1038/nrc887

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc887

Search

Advanced 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