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Arsenic Trioxide and Acute Promyelocytic Leukemia: Clinical and Biological

  • Z. Chen
  • W. -L. Zhao
  • Z. -X. Shen
  • J. -M. Li
  • S. -J. Chen
  • J. Zhu
  • V. Lallemand-Breittenbach
  • J. Zhou
  • M. -C. Guillemin
  • D. Vitoux
  • H. de Thé
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 313)

Abstract

Arsenic has recently been identified as an effective drug in the treatment of newly diagnosed and relapsed acute promyelocytic leukemia. Indeed, arsenic trioxide combined with all-trans retinoic acid shows a synergistic effect. Mechanistically, arsenic targets the key leukemogenic protein PML-RARα, setting up a new example of molecular target-based cancer therapy.

Keywords

Retinoic Acid Acute Promyelocytic Leukemia Complete Remission Rate Arsenic Trioxide Relapse Acute Promyelocytic Leukemia 
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.

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References

  1. Chen GQ, Zhu J, Shi XG, Ni JH, Zhong HJ, Si GY, Jin XL, et al (1996a) 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 down regulation of Bcl-2 expression and modulation of PML-RARalpha/PML proteins. Blood 88:1052–1061PubMedGoogle Scholar
  2. Chen GQ, Shen ZX, Wu F, Han JY, Miao JM, Zhong HJ, Li XS, Zhao JQ, Zhu J, et al (1996b) Pharmacokinetics and efficacy of low-dose all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Leukemia 10:825–828PubMedGoogle Scholar
  3. Chen Z, Wang ZY, Chen SJ (1997) Acute promyelocytic leukemia: cellular and molecular basis of differentiation and apoptosis. Pharmacol Ther 76:141–149PubMedCrossRefGoogle Scholar
  4. de Thé H, Chomienne C, Lanotte M, Degos L, Dejean A (1990) The t(15;17) translocation of acute promyelocytic leukemia fuses the retinoic acid receptor a gene to a novel transcribed locus. Nature 347:558–561PubMedCrossRefGoogle Scholar
  5. de Thé H, Lavau C, Marchio A, Chomienne C, Degos L, Dejean A (1991) The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell 66:675–684PubMedCrossRefGoogle Scholar
  6. Di Croce L, Raker VA, Corsaro M, Fazi F, Fanelli M, Faretta M, Fuks F, Coco FL, Kouzarides T, Nervi C, Minucci S, Pelicci PG (2002) Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295:1079–1082PubMedCrossRefGoogle Scholar
  7. Duprez E, Saurin AJ, Desterro JM, Lallemand-Breitenbach V, Howe K, Boddy MN, Solomon E, de Thé H, Hay RT, Freemont PS (1999) SUMO-1 modification of the acute promyelocytic leukaemia protein PML: implications for nuclear localisation. J Cell Sci 112:381–393PubMedGoogle Scholar
  8. Grignani F, de Matteis S, Nervi C, Tomassoni L, Gelmetti V, Cioce M, Fanelli M, Ruthardt M, Ferrara FF, Zamir I, Seiser C, Grignani F, Lazar MA, Minucci S, Pelicci PG (1998) Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. Nature 391:815–818PubMedCrossRefGoogle Scholar
  9. Hayakawa F, Privalsky ML (2004) Phosphorylation of PML by mitogen-activated protein kinases plays a key role in arsenic trioxide-mediated apoptosis. Cancer Cell 5:389–401PubMedCrossRefGoogle Scholar
  10. He LZ, Guidez F, Tribioli C, Peruzzi D, Ruthardt M, Zelent A, Pandolfi PP (1998) Distinct interactions of PML-RARalpha and PLZF-RARalpha with co-repressors determine differential responses to RA in APL. Nat Genet 18:126–135PubMedCrossRefGoogle Scholar
  11. Jansen JH, Mahfoudi A, Rambaud S, Lavau C, Wahli W, Dejean A (1995) Multimeric complexes of the PML-retinoic acid receptor alpha fusion protein in acute promyelocytic leukemia cells and interference with retinoid and peroxisome-proliferator signaling pathways. Proc Natl Acad Sci USA 92:7401–7405PubMedCrossRefGoogle Scholar
  12. Jing Y, Wang L, Xia L, Chen G, Chen Z, Miller WH, Waxman S (2001) Combined effect of all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia cells in vitro and in vivo. Blood 97:264–269PubMedCrossRefGoogle Scholar
  13. Kamashev DE, Vitoux D, De Thé H (2004) PML-RARA-RXR oligomers mediate retinoid and rexinoid/cAMP in APL cell differentiation. J Exp Med 199:1–13CrossRefGoogle Scholar
  14. Kamitani T, Kito K, Nguyen HP, Wada H, Fukuda-Kamitani T, Yeh ETH (1998a) Identification of three major sentrinization sites in PML. J Biol Chem 41:26675–26682CrossRefGoogle Scholar
  15. Kamitani T, Nguyen HP, Kito K, Fukuda-Kamitani T, Yeh ET (1998b) Covalent modification of PML by the sentrin family of ubiquitin-like proteins. J Biol Chem 273:3117–3120PubMedCrossRefGoogle Scholar
  16. Lallemand-Breitenbach V, Guillemin MC, Janin A, Daniel MT, Degos L, Kogan SC, Bishop JM, de Thé H (1999) Retinoic acid and arsenic synergize to eradicate leukemic cells in a mouse model of acute promyelocytic leukemia. J Exp Med 189:1043–1052PubMedCrossRefGoogle Scholar
  17. Lallemand-Breitenbach V, Zhu J, Puvion F, Koken M, Honore N, Doubeikovsky A, Duprez E, Pandolfi PP, Puvion E, Freemont P, de Thé H (2001) Role of promyelocytic leukemia (PML) sumolation in nuclear body formation, 11S proteasome recruitment, and As(2)O(3)-induced PML or PML/retinoic acid receptor alpha degradation. J Exp Med 193:1361–1372PubMedCrossRefGoogle Scholar
  18. Lazo G, Kantarjian H, Estey E, Thomas D, O’Brien S, Cortes J (2003) Use of arsenic trioxide (As2O3) in the treatment of patients with acute promyelocytic leukemia: the MD Anderson experience. Cancer 97:2218–2224PubMedCrossRefGoogle Scholar
  19. Lin R, Evans R (2000) Acquisition of oncogenic potential by RAR chimeras in acute promyelocytic leukemia through formation of homodimers. Mol Cell 5:821–830PubMedCrossRefGoogle Scholar
  20. Lin RJ, Nagy L, Inoue S, Shao WL, Miller WH, Evans RM (1998) Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature 391:811–814PubMedCrossRefGoogle Scholar
  21. Mathews V, Balasubramanian P, Shaji RV, George B, Chandy M, Srivastava A (2002) Arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: a single center experience. Am J Hematol 70:292–299PubMedCrossRefGoogle Scholar
  22. Miller WH Jr, Schipper HM, Lee JS, Singer J, Waxman S (2002) Mechanisms of action of arsenic trioxide. Cancer Res 62:3893–3903PubMedGoogle Scholar
  23. Minucci S, Maccarana M, Cioce M, De Luca P, Gelmetti V, Segalla S, Di Croce L, Giavara S, Matteucci C, Gobbi A, Bianchini A, Colombo E, Schiavoni I, Badaracco G, Hu X, Lazar MA, Landsberger N, Nervi C, Pelicci PG (2000) Oligomerization of RAR and AML1 transcription factors as a novel mechanism of oncogenic activation. Mol Cell 5:811–820PubMedCrossRefGoogle Scholar
  24. Muller S, Matunis MJ, Dejean A (1998) Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus. EMBO J 17:61–70PubMedCrossRefGoogle Scholar
  25. Nervi C, Poindexter EC, Grignani F, Pandolfi PP, Lo Coco F, Avvisati G, Pelicci PG, Jetten AM (1992) Characterization of the PML-RAR alpha chimeric product of the acute promyelocytic leukemia-specific t(15; 17) translocation. Cancer Res 52:3687–3692PubMedGoogle Scholar
  26. Nervi C, Ferrara FF, Fanelli M, Rippo MR, Tomassini B, Ferrucci PF, Ruthardt M, Gelmetti V, Gambacorti-Passerini C, Diverio D, Grignani F, Pelicci PG, Testi R (1998) Caspases mediate retinoic acid-induced degradation of the acute promyelocytic leukemia PML/RARalpha fusion protein. Blood 92:2244–2251PubMedGoogle Scholar
  27. Niu C, Yan H, Yu T, Sun HP, Liu JX, et al (1999) Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood 94:3315–3324PubMedGoogle Scholar
  28. Perez A, Kastner P, Sethi S, Lutz Y, Reibel C, Chambon P (1993) PML/RAR homodimers: distinct binding properties and heteromeric interactions with RXR. EMBO J 12:3171–3182PubMedGoogle Scholar
  29. Quignon F, Chen Z, de Thé H (1997) Retinoic acid and arsenic: towards oncogene targeted treatments of acute promyelocytic leukaemia. Biochim Biophys Acta 1333:M53–M61PubMedGoogle Scholar
  30. Quignon F, de Bels F, Koken M, Feunteun J, Ameisen JC, de Thé H (1998) PML induces a caspase-independent cell death process. Nat Genet 20:259–265PubMedCrossRefGoogle Scholar
  31. Raffoux E, Rousselot P, Poupon J, Daniel MT, Cassinat B, Delarue R, Taksin AL, Rea D, Buzyn A, Tibi A, Lebbe G, Cimerman P, Chomienne C, Fermand JP, de Thé H, Degos L, Hermine O, Dombret H (2003) Combined treatment with arsenic trioxide and all-trans-retinoic acid in patients with relapsed acute promyelocytic leukemia. J Clin Oncol 21:2326–2334PubMedCrossRefGoogle Scholar
  32. Rego EM, He LZ, Warrell RP Jr, Wang ZG, Pandolfi PP (2000) Retinoic acid (RA) and As2O3 treatment in transgenic models of acute promyelocytic leukemia (APL) unravel the distinct nature of the leukemogenic process induced by the PML-RARalpha and PLZF-RARalpha oncoproteins. Proc Natl Acad Sci US A 97:10173–10178CrossRefGoogle Scholar
  33. Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L, Riganelli D, Zanaria E, Messali S, Cainarca S, Guffanti A, Minucci S, Pelicci PG, Ballabio A (2001) The tripartite motif family identifies cell compartments. EMBO J 20:2140–2151PubMedCrossRefGoogle Scholar
  34. Salomoni P, Pandolfi PP (2002) The role of PML in tumor suppression. Cell 108:165–170PubMedCrossRefGoogle Scholar
  35. Seeler JS, Dejean A (2001) SUMO: of branched proteins and nuclear bodies. Oncogene 20:7243–7249PubMedCrossRefGoogle Scholar
  36. Shen Y, Shen ZX, Yan H, Chen J, Zeng XY, Li JM, Li XS, Wu W, Xiong SM, Zhao WL, Tang W, Wu F, Liu YF, Niu C, Wang ZY, Chen SJ, Chen Z (2001) Studies on the clinical efficacy and pharmacokinetics of low-dose arsenic trioxide in the treatment of relapsed acute promyelocytic leukemia: a comparison with conventional dosage. Leukemia 15:735–741PubMedCrossRefGoogle Scholar
  37. Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY, Zhu J, Tang W, Sun GL, Yang KQ, Chen Y, Zhou L, Fang ZW, Wang YT, Ma J, Zhang P, Zhang TD, Chen SJ, Chen Z, Wang ZY (1997) Use of arsenic trioxide (As203) in the treatment of acute promyelocytic leukemia (APL). II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 89:3354–3360PubMedGoogle Scholar
  38. Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM, Shi JY, Zheng PZ, Yan H, Liu YF, Chen Y, Shen Y, Wu W, Tang W, Waxman S, De The H, Wang ZY, Chen SJ, Chen Z (2004) 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 101:5328–5335PubMedCrossRefGoogle Scholar
  39. Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E, Stone RM, Kalaycio M, Scheinberg DA, Steinherz P, Sievers EL, Coutre S, Dahlberg S, Ellison R, Warrell RP Jr (2001) United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 19:3852–3860PubMedGoogle Scholar
  40. Sun HD, Ma L, Hu HX, Zhang TD (1992) 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. Zhongguo Zhong Xi Yi Jie He Za Zhi 12:170–171Google Scholar
  41. Wang ZG, Ruggero D, Ronchetti S, Zhong S, Gaboli M, Rivi R, Pandolfi PP (1998a) PML is essential for multiple apoptotic pathways. Nat Genet 20:266–272PubMedCrossRefGoogle Scholar
  42. Wang ZG, Delva L, Gaboli M, Rivi R, Giorgio M, Cordon-Cardo C, Grosveld F, Pandolfi PP (1998b) Role of PML in cell growth and the retinoic acid pathway. Science 279:1547–1551PubMedCrossRefGoogle Scholar
  43. Warrell R, de Thé H, Wang Z, Degos L (1993) Acute promyelocytic leukemia. N Engl J Med 329:177–189PubMedCrossRefGoogle Scholar
  44. Zhang P, Wang SY, Hu XH, et al (1996) Arsenic trioxide-treated 72 cases of acute promyelocytic leukemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi 17:58–60Google Scholar
  45. Zhang P, Wang S, Hu L, Qiu F, Yang H, Xiao Y, Li X, Han X, Zhou J, Liu P (2000) Seven years’ summary report on the treatment of acute promyelocytic leukemia with arsenic trioxide—an analysis of 242 cases (in Chinese). Zhonghua Xue Ye Xue Za Zhi 21:67–70PubMedGoogle Scholar
  46. Zheng PZ, Wang KK, Zhang QY, Huang QH, Du YZ, Zhang QH, Xiao DK, Shen SH, Imbeaud S, Eveno E, Zhao CJ, Chen YL, Fan HY, Waxman S, Auffray C, Jin G, Chen SJ, Chen Z, Zhang J (2005) 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 102:7653–7658PubMedCrossRefGoogle Scholar
  47. Zhou GB, Zhao WL, Wang ZY, Chen SJ, Chen Z (2005) Retinoic acid and arsenic for treating acute promyelocytic leukemia. PLoS Med 2:12CrossRefGoogle Scholar
  48. Zhu J, Koken MHM, Quignon F, Chelbi-Alix MK, Degos L, Wang ZY, Chen Z, de Thé H (1997) Arsenic-induced PML targeting onto nuclear bodies: implications for the treatment of acute promyelocytic leukemia. Proc Natl Acad Sci USA 94:3978–3983PubMedCrossRefGoogle Scholar
  49. Zhu J, Gianni M, Kopf E, Honore N, Chelbi-Alix M, Koken M, Quignon F, Rochette-Egly C, de Thé H (1999) Retinoic acid induces proteasome-dependent degradation of retinoic acid receptor alpha (RAR alpha) and oncogenic RAR alpha fusion proteins. Proc Natl Acad Sci U S A 96:14807–14812PubMedCrossRefGoogle Scholar
  50. Zhu J, Lallemand-Breitenbach V, de Thé H (2001) Pathways of retinoic acid-or arsenic trioxide-induced PML/RARalpha catabolism, role of oncogene degradation in disease remission. Oncogene 20:7257–7265PubMedCrossRefGoogle Scholar
  51. Zhu J, Chen Z, Lallemand-Breitenbach V, de Thé H (2002a) How acute promyelocytic leukemia revived arsenic. Nat Rev Cancer 2:705–713PubMedCrossRefGoogle Scholar
  52. Zhu Q, Zhang JW, Zhu HQ, Shen YL, Flexor M, Jia PM, Yu Y, Cai X, Waxman S, Lanotte M, Chen SJ, Chen Z, Tong JH (2002b) Synergic effects of arsenic trioxide and cAMP during acute promyelocytic leukemia cell maturation subtends a novel signaling cross-talk. Blood 99:1014–1022PubMedCrossRefGoogle Scholar
  53. Zhu J, Zhou J, Peres L, Riaucoux F, Honore N, Kogan S, de Thé H (2005) A sumoylation site in PML/RARAis essential for leukemic transformation. Cancer Cell 7:143–153PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2007

Authors and Affiliations

  • Z. Chen
    • 1
  • W. -L. Zhao
    • 1
  • Z. -X. Shen
    • 1
  • J. -M. Li
    • 1
  • S. -J. Chen
    • 1
  • J. Zhu
    • 1
    • 2
  • V. Lallemand-Breittenbach
    • 2
  • J. Zhou
    • 1
    • 2
  • M. -C. Guillemin
    • 2
  • D. Vitoux
    • 2
  • H. de Thé
    • 2
  1. 1.Shanghai Institute of Hematology, Rui Jin Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiPeople’s Republic of China
  2. 2.Hôpital St. LouisCNRS UMR 7151 Université de Paris VIIParisFrance

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