Skip to main content

Acute Promyelocytic Leukemia

  • Chapter
  • First Online:
Neoplastic Diseases of the Blood

Abstract

Acute promyelocytic leukemia (APL) is designated M3 in the French-American-British (FAB) classification. Because of its unique clinical features and unique response to certain differentiation inducing agents, and because of our advanced understanding of the molecular biology of this leukemia, APL deserves to be presented and discussed in detail, apart from the other acute myeloid leukemias.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 269.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Hillestad L. Acute promyelocytic leukemia. Acta Med Scand. 1957;159:189.

    Article  PubMed  CAS  Google Scholar 

  2. Stavem P. Acute hypergranular promyelocytic leukemia. Priority of discovery. Scand J Haematol. 1978;20:287.

    PubMed  CAS  Google Scholar 

  3. Caen J, Mathe G, Xuan Chat L, Bernard J. Etude de la fibrinolyse au cours des hémopathies malignes. In: Transactions of the 6th Congress of the European Society of Hématology. Basel: Karger; 1957: 502

    Google Scholar 

  4. Bernard J, Mathe G, Boulay J, Ceoura B. La leucose aiguë à promyélocytes. Etude portant sur 20 observations. J Suisse Med. 1959;23:604.

    Google Scholar 

  5. Bernard J, Weil M, Boiron M, et al. Acute promyelocytic leukemia. Results of treatment with daunorubicin. Blood. 1973;41:489.

    PubMed  CAS  Google Scholar 

  6. Golomb HM, Rowley JD, Vardiman J, et al. Partial deletion of long arm of chromosome 7. A specific abnormality in acute promyelocytic leukemia? Arch Intern Med. 1976;136:825.

    Article  PubMed  CAS  Google Scholar 

  7. Rowley J, Golomb H, Dougherty C. 15/17 translocation: A consistent chromosomal change in acute promyelocytic leukemia. Lancet. 1977;1:549.

    Article  PubMed  CAS  Google Scholar 

  8. Larson RA, Kondo K, Vardiman JW, et al. Evidence for a 15;17 translocation in every patient with acute promyelocytic leukemia. Am J Med. 1984;76:827.

    Article  PubMed  CAS  Google Scholar 

  9. Kantarjian HM, Keating MJ, Walters RS, et al. Acute promyelocytic leukemia. M.D. Anderson Hospital experience. Am J Med. 1986;80:789.

    Article  PubMed  CAS  Google Scholar 

  10. Stone RM, Maguire M, Goldberg MA, et al. Complete remission in acute promyelocytic leukemia despite persistence of abnormal bone marrow promyelocytes during induction therapy: Expertonce in 34 patients. Blood. 1988;71:690.

    PubMed  CAS  Google Scholar 

  11. Brittan T, Selznick S, Collins S. Induction of differentiation of the human promyelocytic leukemic cell line (HL-60) by retinoic acid. Proc Natl Acad Sci USA. 1980;77:2936.

    Article  Google Scholar 

  12. Huang M-E, Ye Y-C, Chen S-R, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood. 1988;72:567.

    PubMed  CAS  Google Scholar 

  13. Fenaux P, Chas tang C, Degas L. Treatment of newly diagnosed acute promyelocytic leukemia (APL) by a combination of alltrans retinoic acid (ATRA) and chemotherapy. Leukemia. 1994;8 Suppl 2:S42.

    PubMed  Google Scholar 

  14. Chen GQ, Shi XG, Tang W, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): I. As203 exerts dose-dependent dual effects on APL cells. Blood. 1997;89:3345.

    PubMed  CAS  Google Scholar 

  15. Wiernik PH. Acute promyelocytic leukemia: another pseudoleukemia? Blood. 1990;76:1675.

    PubMed  CAS  Google Scholar 

  16. Degos L. Is acute promyelocytic leukemia a curable disease? Treatment strategy for a long-term survival. Leukemia. 1994;8:S6.

    PubMed  Google Scholar 

  17. Bernard J. History of promyelocytic leukemia. Leukemia. 1994;8 Suppl 2:1.

    Google Scholar 

  18. Breitman TR, Collins SJ, Keene BR. Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acid. Blood. 1981;57:1000–4.

    PubMed  CAS  Google Scholar 

  19. Huang M-e, Ye Y-c, Chen S-r, Chai J-r, Lu J-X, Lin Z, et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood. 1988;72:567–72.

    PubMed  CAS  Google Scholar 

  20. Borrow J, Goddard AD, Sheer D, Solomon E. Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17. Science. 1990;249:1577–80.

    Article  PubMed  CAS  Google Scholar 

  21. de The H, Chomienne C, Lanotte M, Degos L, Dejean A. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor Ë gene to a novel transcribed locus. Nature. 1990;347:558–61.

    Article  PubMed  Google Scholar 

  22. Longo L, Pandolfi P, Biondi A, Rambaldi A, Mencarelli A, Lo Coco F, et al. Rearrangements and aberrant expression of the retinoic acid receptor Ï gene in acute promyelocytic leukemias. J Exp Med. 1990;172:1571–5.

    Article  PubMed  CAS  Google Scholar 

  23. Petkovich M, Brand NJ, Krust A, Chambon P. A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature. 1987;330:444–50.

    Article  PubMed  CAS  Google Scholar 

  24. Giguere V, Ong ES, Segui P, Evans RM. Identification of a receptor for the morphogen retinoic acid. Nature. 1987;330:624–9.

    Article  PubMed  CAS  Google Scholar 

  25. de The H, Lavau C, Marchio A, Chomienne C, Degos L, Dejean A. The PML-RARa fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell. 1991;66:675–84.

    Article  PubMed  Google Scholar 

  26. Kakizuka A, Miller Jr WH, Umesono K, Warrell Jr RP, Frankel SR, Murty VVVS, et al. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RARa with a novel putative transcription factor, PML. Cell. 1991;66:663–74.

    Article  PubMed  CAS  Google Scholar 

  27. Pandolfi P, Grignani F, Alcalay M, Mencarelli A, Biondi A, LoCoco F, et al. Structure and origin of the acute promyelocytic leukemia myl/RARa cDNA and characterization of its retinoid-binding and transactivation properties. Oncogene. 1991;6:1285–92.

    PubMed  CAS  Google Scholar 

  28. Chen Z, Brand N, Chen A, Chen S, Tong J, Wang 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 associated with acute promyelocytic leukemia. EMBO J. 1993;12:1161–72.

    PubMed  CAS  Google Scholar 

  29. Redner RL, Chen JD, Rush EA, Li H, Pollock SL. The t(5;17) acute promyelocytic leukemia fusion protein NPM-RAR interacts with co-repressor and co-activator proteins and exhibits both positive and negative transcriptional properties. Blood. 2000;95:2683–90.

    PubMed  CAS  Google Scholar 

  30. Wells RA, Catzavelos C, Kamel-Reid S. Fusion of retinoic acid receptor a to NuMA, the nuclear mitotic apparatus protein by a variant translocation in acute promyelocytic leukemia. Nat Genet. 1997;17:109–13.

    Article  PubMed  CAS  Google Scholar 

  31. Arnould C, Philippe C, Bourdon V, Gregoire MJ, Berger R, Jonveaux P. The signal transducer and activator of transcription STAT5b gene is a new partner of retinoic acid receptor a in acute promyelocytic-like leukaemia. Hum Mol Genet. 1999;8:1741–9.

    Article  PubMed  CAS  Google Scholar 

  32. Catalano A, Dawson MA, Somana K, Opat S, Schwarer A, Campbell LJ, et al. The PRKAR1A gene is fused to RARA in a new variant acute promyelocytic leukemia. Blood. 2007;110(12):4073–6.

    Article  PubMed  CAS  Google Scholar 

  33. 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(9):1414–6.

    Article  PubMed  CAS  Google Scholar 

  34. Zelent A, Guidez F, Melnick A, Waxman S, Licht JD. Translocations of the RARalpha gene in acute promyelocytic leukemia. Oncogene. 2001;20(49):7186–203.

    Article  PubMed  CAS  Google Scholar 

  35. Scaglioni PP, Pandolfi PP. The theory of APL revisited. Curr Top Microbiol Immunol. 2007;313:85–100.

    Article  PubMed  CAS  Google Scholar 

  36. Chen GQ, Zhu J, Shi XG, Zhong HJ, Ni JH, Si GY, 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 alteration of PML-RARa/PML protein localization. Blood. 1996;88:1052–61.

    PubMed  CAS  Google Scholar 

  37. Chen GQ, Shi XG, Tang W, Xiong SM, Zhu J, Cai X, 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. 1997;89:3345–53.

    PubMed  CAS  Google Scholar 

  38. Lanotte M, Martin-Thouvenin B, Najman S, Balerini P, Valensi F, Berger R. NB4, a maturation inducible cell line with t(15;17) marker isolated from a human acute promyelocytic leukemia (M3). Blood. 1991;77(5):1080–6.

    PubMed  CAS  Google Scholar 

  39. Gallagher R, Collins S, Trujillo J, McCredie K, Ahearn M, Tsai S, et al. Characterization of the continuous, differentiating myeloid leukemia cell line (HL-60) from a patient with acute promyelocytic leukemia. Blood. 1979;54:713–33.

    PubMed  CAS  Google Scholar 

  40. Breitman T, Selonick S, Collins S. Induction of differentiation of the human promyelocytic leukemic cell line (HL-60) by retinoic acid. Proc Natl Acad Sci USA. 1980;77:2936–40.

    Article  PubMed  CAS  Google Scholar 

  41. Kogan SC. Mouse models of acute promyelocytic leukemia. Curr Topics Microbiol Immunol. 2007;313:3–29.

    Article  CAS  Google Scholar 

  42. Nasr R, Guillemin MC, Ferhi O, Soilihi H, Peres L, Berthier C, et al. Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation. Nat Med. 2008;14(12):1333–42.

    Article  PubMed  CAS  Google Scholar 

  43. Wojiski S, Guibal FC, Kindler T, Lee BH, Jesneck JL, Fabian A, et al. PML-RARalpha initiates leukemia by conferring properties of self-renewal to committed promyelocytic progenitors. Leukemia. 2009;23(8):1462–71.

    Article  PubMed  CAS  Google Scholar 

  44. Guibal FC, Alberich-Jorda M, Hirai H, Ebralidze A, Levantini E, Di Ruscio A, et al. Identification of a myeloid committed progenitor as the cancer-initiating cell in acute promyelocytic leukemia. Blood. 2009;114(27):5415–25.

    Article  PubMed  CAS  Google Scholar 

  45. Chambon P. A decade of molecular biology of retinoic acid receptors. FASEB J. 1996;10:940–54.

    PubMed  CAS  Google Scholar 

  46. Kurokawa R, DiRenzo J, Boehm M, Sugarman J, Gloss B, Rosenfeld M, et al. Regulation of retinoid signalling by receptor polarity and allosteric control of ligand binding. Nature. 1994;371:528–31.

    Article  PubMed  CAS  Google Scholar 

  47. Renaud J-P, Rochel N, Ruff M, Vivat V, Chambon P, Gronemeyer H, et al. Crystal structure of the RAR-g ligand binding domain bound to all-trans retinoic acid. Nature. 1995;378:681–9.

    Article  PubMed  CAS  Google Scholar 

  48. Perissi V, Staszewski LM, McInerney EM, Kurokawa R, Krones A, Rose DW, et al. Molecular determinants of nuclear receptor-corepressor interaction. Genes Dev. 1999;13:3198–208.

    Article  PubMed  CAS  Google Scholar 

  49. Kouzarides T. Chromatin modifications and their function. Cell. 2007;128(4):693–705.

    Article  PubMed  CAS  Google Scholar 

  50. Yang XJ, Seto E. Lysine acetylation: codified crosstalk with other posttranslational modifications. Mol Cell. 2008;31(4):449–61.

    Article  PubMed  CAS  Google Scholar 

  51. Huq MD, Tsai NP, Khan SA, Wei LN. Lysine trimethylation of retinoic acid receptor-alpha: a novel means to regulate receptor function. Mol Cell Proteomics. 2007;6(4):677–88.

    Article  PubMed  CAS  Google Scholar 

  52. Chen H, Lin RJ, Xie W, Wilpitz D, Evans RM. Regulation of hormone-induced histone hyperacetylation and gene activation via acetylation of an acetylase. Cell. 1999;98(5):675–86.

    Article  PubMed  CAS  Google Scholar 

  53. Bastien J, Rochette-Egly C. Nuclear retinoid receptors and the transcription of retinoid-target genes. Gene. 2004;328:1–16.

    Article  PubMed  CAS  Google Scholar 

  54. Narlikar GJ, Fan HY, Kingston RE. Cooperation between complexes that regulate chromatin structure and transcription. Cell. 2002;108(4):475–87.

    Article  PubMed  CAS  Google Scholar 

  55. Ho L, Crabtree GR. Chromatin remodelling during development. Nature. 2010;463(7280):474–84.

    Article  PubMed  CAS  Google Scholar 

  56. Strahl BD, Allis CD. The language of covalent histone modification. Nature. 1998;403:41–5.

    Google Scholar 

  57. Jensen K, Shiels C, Freemont PS. PML protein isoforms and the RBCC/TRIM motif. Oncogene. 2001;20(49):7223–33.

    Article  PubMed  CAS  Google Scholar 

  58. Borden KL. Pondering the puzzle of PML (promyelocytic leukemia) nuclear bodies: can we fit the pieces together using an RNA regulon? Biochim Biophys Acta. 2008;1783(11):2145–54.

    Article  PubMed  CAS  Google Scholar 

  59. Daniel M, Koken M, Romagne O, Barbey S, Bazarbachi A, Stadler M, et al. PML protein expression in hematopoietic and acute promyleocytic leukemia cells. Blood. 1993;82:1858–67.

    PubMed  CAS  Google Scholar 

  60. Terris B, Baldin V, Dubois S, Degott C, Flejou J-F, Henin D, et al. PML nuclear bodies are general targets for inflammation and cell proliferation. Cancer Res. 1995;55:1590–7.

    PubMed  CAS  Google Scholar 

  61. Bernardi R, Pandolfi PP. Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies. Nat Rev Mol Cell Biol. 2007;8:1006–16.

    Article  PubMed  CAS  Google Scholar 

  62. Van Damme E, Laukens K, Dang TH, Van Ostade X. A manually curated network of the PML nuclear body interactome reveals an important role for PML-NBs in SUMOylation dynamics. Int J Biol Sci. 2010;6(1):51–67.

    Article  PubMed  Google Scholar 

  63. Zhong S, Muller S, Ronchetti S, Freemont PS, Dejean A, Pandolfi PP. Role of SUMO-1-modified PML in nuclear body formation. Blood. 2000;95:2748–52.

    PubMed  CAS  Google Scholar 

  64. Lallemand-Breitenbach V, Jeanne M, Benhenda S, Nasr R, Lei M, Peres L, et al. Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nat Cell Biol. 2008;10(5):547–55.

    Article  PubMed  CAS  Google Scholar 

  65. Tatham MH, Geoffroy MC, Shen L, Plechanovova A, Hattersley N, Jaffray EG, et al. RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat Cell Biol. 2008;10(5):538–46.

    Article  PubMed  CAS  Google Scholar 

  66. Reineke EL, Kao HY. Targeting promyelocytic leukemia protein: a means to regulating PML nuclear bodies. Int J Biol Sci. 2009;5(4):366–76.

    Article  PubMed  CAS  Google Scholar 

  67. Wang ZG, Delva L, Gaboli M, Rivi R, Giorgio M, Cordon-Cardo C, et al. Role of PML in cell growth and the retinoic acid pathway. Science. 1998;279:1547–51.

    Article  PubMed  CAS  Google Scholar 

  68. Bernardi R, Papa A, Pandolfi PP. Regulation of apoptosis by PML and the PML-NBs. Oncogene. 2008;27(48):6299–312.

    Article  PubMed  CAS  Google Scholar 

  69. Gurrieri C, Capodieci P, Bernardi R, Scaglioni PP, Nafa K, Rush LJ, et al. Loss of the tumor suppressor PML in human cancers of multiple histologic origins. J Natl Cancer Inst. 2004;96(4):269–79.

    Article  PubMed  CAS  Google Scholar 

  70. Ito K, Bernardi R, Morotti A, Matsuoka S, Saglio G, Ikeda Y, et al. PML targeting eradicates quiescent leukaemia-initiating cells. Nature. 2008;453(7198):1072–8.

    Article  PubMed  CAS  Google Scholar 

  71. Borden KLB, Boddy MN, Lally J, O’Reilly NJ, Martin S, Howe K, et al. The solution structure of the RING finger domain from the acute promyelocytic leukaemia proto-oncoprotein PML. EMBO J. 1995;14:1532–41.

    PubMed  CAS  Google Scholar 

  72. Slack JL, Willman CL, Andersen JW, Li Y-P, Viswanatha DS, Bloomfield CD, et al. Molecular analysis and clinical outcome of adult APL patients with the type V PML-RARa isoform: results from Intergroup protocol 0129. Blood. 2000;95:398–403.

    PubMed  CAS  Google Scholar 

  73. Gu BW, Xiong H, Zhou Y, Chen B, Dong S, Yu ZY, et al. Variant-type PML-RARa fusion transcript in acute promyelocytic leukemia: use of a cryptic coding sequence from intron 2 of the RARa gene and identification of a new clinical subtype of retinoic acid therapy. Proc Natl Acad Sci USA. 2002;99:7640–5.

    Article  PubMed  CAS  Google Scholar 

  74. Reiter A, Saussele S, Grimwade D, Wiemels JL, Segal MR, Lafage-Pochitaloff M, et al. Genomic anatomy of the specific reciprocal translocation t(15;17) in acute promyelocytic leukemia. Genes Chromosomes Cancer. 2003;36(2):175–88.

    Article  PubMed  CAS  Google Scholar 

  75. Gallagher RE, Willman CL, Slack JL, Andersen JW, Li YP, Viswanatha D, et al. Association of PML-RARa fusion mRNA type with pretreatment hematologic characteristics but not treatment outcome in acute promyelocytic leukemia: An intergroup molecular study. Blood. 1997;90:1656–63.

    PubMed  CAS  Google Scholar 

  76. Kane JR, Head DR, Balazs L, Hulshof MG, Motroni TA, Raimondi SC, et al. Molecular analysis of the PML/RAR alpha chimeric gene in pediatric acute promyelocytic leukemia. Leukemia. 1996;10(8):1296–302.

    PubMed  CAS  Google Scholar 

  77. Guglielmi C, Martelli MP, Diverio D. Immunophenotype of adult and childhood acute promyelocytic leukaemia: correlation with morphology, type of PML gene breakpoint and clinical outcome: a cooperative Italian study on 196 cases. Br J Haematol. 1998;102:1035–10941.

    Article  PubMed  CAS  Google Scholar 

  78. Alcalay M, Zangrilli D, Fagioli M, Pandolfi P, Mencarelli A, Lo Coco F, et al. Expression pattern of the RARa-PML fusion gene in acute promyelocytic leukemia. Proc Natl Acad Sci USA. 1992;89:4840–4.

    Article  PubMed  CAS  Google Scholar 

  79. Borrow J, Goddard AD, Gibbons B, Katz F, Swirsky D, Fioretos T, et al. Diagnosis of acute promyelocytic leukaemia by RT-PCR detection of PML-RARA and RARA-PML fusion transcripts. Br J Haematol. 1992;82:529–40.

    Article  PubMed  CAS  Google Scholar 

  80. Li YP, Andersen J, Zelent A, Rao S, Paietta E, Tallman MS, et al. RARa1/RARa2-PML mRNA expression in acute promyelocytic leukemia cells: A molecular and laboratory-clinical correlative study. Blood. 1997;90:306–12.

    PubMed  CAS  Google Scholar 

  81. Walz C, Grimwade D, Saussele S, Lengfelder E, Hafelach C, Schnittger S, et al. Atypical mRNA fusions in PML-RARA positive, RARA-PML negative acute promyelocytic leukemia. Genes Chromosomes Cancer. 2010;49:471–9.

    PubMed  CAS  Google Scholar 

  82. Mistry AR, Felix CA, Whitmarsh RJ, Mason A, Reiter A, Cassinat B, et al. DNA topoisomerase II in therapy-related acute promyelocytic leukemia. N Engl J Med. 2005;352(15):1529–38.

    Article  PubMed  CAS  Google Scholar 

  83. Hasan SK, Mays AN, Ottone T, Ledda A, La Nasa G, Cattaneo C, et al. Molecular analysis of t(15;17) genomic breakpoints in ­secondary acute promyelocytic leukemia arising after treatment of multiple sclerosis. Blood. 2008;112(8):3383–90.

    Article  PubMed  CAS  Google Scholar 

  84. Mays AN, Osheroff N, Xiao Y, Wiemels JL, Felix CA, Byl JA, et al. Evidence for direct involvement of epirubicin in the formation of chromosomal translocations in t(15;17) therapy-related acute promyelocytic leukemia. Blood. 2010;115(2):326–30.

    Article  PubMed  CAS  Google Scholar 

  85. McHale CM, Wiemels JL, Zhang L, Ma X, Buffler PA, Feusner J, et al. Prenatal origin of childhood acute myeloid leukemias harboring chromosomal rearrangements t(15;17) and inv(16). Blood. 2003;101(11):4640–1.

    Article  PubMed  CAS  Google Scholar 

  86. Collins SJ. Acute promyelocytic leukemia: relieving repression induces remission. Blood. 1998;91(8):2631–3.

    PubMed  CAS  Google Scholar 

  87. Lin RJ, Evans RM. Acquisition of oncogenic potential by RAR chimeras in acute promyelocytic leukemia through formation of homodimers. Mol Cell. 2000;5:821–30.

    Article  PubMed  CAS  Google Scholar 

  88. Onodera M, Kunisada T, Nishikawa S, Sakiyama Y, Matsumoto S, Nishikawa S. Overexpression of retinoic acid receptor alpha suppresses myeloid cell differentiation at the promyelocyte stage. Oncogene. 1995;11:1291–8.

    PubMed  CAS  Google Scholar 

  89. Du C, Redner RL, Cooke MP, Lavau C. Overexpression of wild-type retinoic acid receptor alpha (RARalpha) recapitulates retinoic acid-sensitive transformation of primary myeloid progenitors by acute promyelocytic leukemia RARalpha-fusion genes. Blood. 1999;94:793–802.

    PubMed  CAS  Google Scholar 

  90. Robertson K, Emami B, Collins S. Retinoic acid-resistant HL-60R cells harbor a point mutation in the retinoic acid receptor ligand-binding domain that confers dominant negative activity. Blood. 1992;80:1885–8.

    PubMed  CAS  Google Scholar 

  91. Grignani F, Valtieri M, Gabbianelli M, Gelmetti V, Botta R, Luchetti L, et al. PML/RARa fusion protein expression in normal human hematopoietic progenitors dictates myeloid commitment and the promyelocytic phenotype. Blood. 2000;96:1531–7.

    PubMed  CAS  Google Scholar 

  92. Yoshida H, Kitamura K, Tanaka K, Omura S, Miyazaki T, Hachiya T, et al. Accelerated degradation of PML-retinoic acid receptor a (PML-RARA) oncoprotein by all-trans retinoic acid in acute promyelocytic leukemia: Possible role of the proteasome pathway. Cancer Res. 1996;56:2945–8.

    PubMed  CAS  Google Scholar 

  93. Zhu J, Gianni M, Kopf E, Honore N, Chelbi-Alix M, Koken M, et al. Retinoic acid induces proteasome-dependent degradation of retinoic acid receptor a (RARa) and oncogenic RARa fusion proteins. Proc Natl Acad Sci USA. 1999;96:14807–12.

    Article  PubMed  CAS  Google Scholar 

  94. Lin RJ, Nagy L, Inoue S, Shao W, Miller Jr WH, Evans RM. Role of the histone deacetylase complex in acute promyelocytic leukemia. Nature. 1998;391:811–4.

    Article  PubMed  CAS  Google Scholar 

  95. Grignani F, De Matteis S, Nervi C, Tomassoni L, Gelmetti V, Cioce M, et al. Fusion proteins of the retinoic acid receptor-a recruit histone deacetylase in promyelocytic leukemia. Nature. 1998;391:815–7.

    Article  PubMed  CAS  Google Scholar 

  96. Guidez F, Ivins S, Zhu J, Soderstrom M, Waxman S, Zelent A. Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML- and PLZF-RARa underlie molecular pathogenesis and treatment of acute promyelocytic leukemia. Blood. 1998;91:2634–42.

    PubMed  CAS  Google Scholar 

  97. Di Croce L, Raker VA, Corsaro M, Faxi F, Fanelli M, Faretta M, et al. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science. 2002;295:1079–82.

    Article  PubMed  Google Scholar 

  98. Carbone R, Botrugno OA, Ronzoni S, Insinga A, Di Croce L, Pelicci PG, 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(4):1288–96.

    Article  PubMed  CAS  Google Scholar 

  99. Villa R, Morey L, Raker VA, Buschbeck M, Gutierrez A, De Santis F, et al. The methyl-CpG binding protein MBD1 is required for PML-RAR alpha function. Proc Natl Acad Sci USA. 2006;103(5):1400–5.

    Article  PubMed  CAS  Google Scholar 

  100. Villa R, Pasini D, Gutierrez A, Morey L, Occhionorelli M, Vire E, et al. Role of the polycomb repressive complex 2 in acute promyelocytic leukemia. Cancer Cell. 2007;11(6):513–25.

    Article  PubMed  CAS  Google Scholar 

  101. Morey L, Brenner C, Fazi F, Villa R, Gutierrez A, Buschbeck M, et al. MBD3, a component of the NuRD complex, facilitates chromatin alteration and deposition of epigenetic marks. Mol Cell Biol. 2008;28(19):5912–23.

    Article  PubMed  CAS  Google Scholar 

  102. Kogan SC, Hong SH, Shultz DB, Privalsky ML, Bishop JM. Leukemia initiated by PMLRARa: the PML domain plays a critical role while retinoic acid-mediated transactivation is dispensable. Blood. 2000;95:1541–50.

    PubMed  CAS  Google Scholar 

  103. Matsushita H, Scaglioni PP, Bhaumik M, Rego EM, Cai LF, Majid SM, et al. In vivo analysis of the role of aberrant histone deacetylase recruitment and RAR alpha blockade in the pathogenesis of acute promyelocytic leukemia. J Exp Med. 2006;203(4):821–8.

    Article  PubMed  CAS  Google Scholar 

  104. Sternsdorf T, Phan VT, Maunakea ML, Ocampo CB, Sohal J, Silletto A, et al. Forced retinoic acid receptor a homodimers prime mice for APL-like leukemia. Cancer Cell. 2006;9:81–94.

    Article  PubMed  CAS  Google Scholar 

  105. Kwok C, Zeisig BB, Dong S, So CW. Forced homo-oligomerization of RARalpha leads to transformation of primary hematopoietic cells. Cancer Cell. 2006;9(2):95–108.

    Article  PubMed  CAS  Google Scholar 

  106. Licht JD. Reconstructing a disease: what essential features of the retinoic acid receptor fusion oncoproteins generate actue promyelocytic leukemia? Cancer Cell. 2006;9:73–4.

    Article  PubMed  CAS  Google Scholar 

  107. Koken MHM, Reid A, Quignon F, Chelbi-Alix MK, Dong S, Chen S-J, et al. Leukaemia-associated RARa fusion partners, PML and PLZF, heterodimerize and co-localize onto nuclear bodies. Proc Natl Acad Sci USA. 1997;94:10255–60.

    Article  PubMed  CAS  Google Scholar 

  108. Zhu J, Zhou J, Peres L, Riaucoux F, Honore N, Kogan SC, et al. A sumoylation site in PML/RARA is essential for leukemic transformation. Cancer Cell. 2005;7:143–53.

    Article  PubMed  CAS  Google Scholar 

  109. Rego EM, Wang ZG, Peruzzi D, He LZ, Cordon-Cardo C, Pandolfi PP. Role of promyelocytic leukemia (PML) protein in tumor suppression. J Exp Med. 2001;193:521–9.

    Article  PubMed  CAS  Google Scholar 

  110. Koken MHM, Puvion-Dutilleul F, Guillemin MC, Viron A, Linares-Cruz G, Stuurman N, et al. The t(15;17) translocation alters a nuclear body in a retinoic acid-reversible fashion. EMBO J. 1994;13:1073–83.

    PubMed  CAS  Google Scholar 

  111. Zeisig BB, Kwok C, Zelent A, Shankaranarayanan P, Gronemeyer H, Dong S, et al. Recruitment of RXR by homotetrameric RARalpha fusion proteins is essential for transformation. Cancer Cell. 2007;12(1):36–51.

    Article  PubMed  CAS  Google Scholar 

  112. Zhu J, Nasr R, Peres L, Riaucoux-Lormiere F, Honore N, Berthier C, et al. RXR is an essential component of the oncogenic PML/RARA complex in vivo. Cancer Cell. 2007;12(1):23–35.

    Article  PubMed  CAS  Google Scholar 

  113. Minucci S, Pelicci PG. Determinants of oncogenic transformation in acute promyelocytic leukemia: the hetero-union makes the force. Cancer Cell. 2007;12(1):1–3.

    Article  PubMed  CAS  Google Scholar 

  114. Zimonjic DB, Pollock JL, Westervelt P, Popescu NC, Ley TJ. Acquired, nonrandom chromosomal abnormalities associated with the development of acute promyelocytic leukemia in transgenic mice. Proc Natl Acad Sci USA. 2000;97(24):13306–11.

    Article  PubMed  CAS  Google Scholar 

  115. Le Beau MM, Bitts S, Davis EM, Kogan SC. Recurring chromosomal abnormalities in leukemia in PML-RARA transgenic mice parallel human acute promyelocytic leukemia. Blood. 2002;99(8):2985–91.

    Article  PubMed  Google Scholar 

  116. Walter MJ, Park JS, Lau SKM, Li X, Lane AA, Nagarajan R, et al. Expression profiling of murine acute promyelocytic leukemia cells reveals multiple model-dependent progression signatures. Mol Cell Biol. 2004;24:10882–93.

    Article  PubMed  CAS  Google Scholar 

  117. Walter MJ, Park JS, Ries RE, Lau SK, McLellan M, Jaeger S, et al. Reduced PU.1 expression causes myeloid progenitor expansion and increased leukemia penetrance in mice expressing PML-RARalpha. Proc Natl Acad Sci USA. 2005;102(35):12513–8.

    Article  PubMed  CAS  Google Scholar 

  118. Kelly LM, Kutok JL, Williams IR, Boulton CL, Amarat SM, Curley DP, et al. PML/RARa and FLT3-ITD induce an APL-like disease in a mouse model. Proc Natl Acad Sci USA. 2002;99:8283–8.

    Article  PubMed  CAS  Google Scholar 

  119. Chan IT, Kutok JL, Williams IR, Cohen S, Moore S, Shigematsu H, et al. Oncogenic K-ras cooperates with PML-RAR alpha to induce an acute promyelocytic leukemia-like disease. Blood. 2006;108(5):1708–15.

    Article  PubMed  CAS  Google Scholar 

  120. Westervelt P, Lane AA, Pollock JL, Oldfather K, Holt MS, Zimonjic DB, et al. High-penetrance mouse model of acute promyelocytic leukemia with very low levels of PML-RARa expression. Blood. 2003;102:1857–65.

    Article  PubMed  CAS  Google Scholar 

  121. Lane AA, Ley TJ. Neutrophil elastase is important for PML-retinoic acid receptor alpha activities in early myeloid cells. Mol Cell Biol. 2005;25(1):23–33.

    Article  PubMed  CAS  Google Scholar 

  122. Alcalay M, Meani N, Gelmetti V, Fantozzi A, Fagioli M, Orleth A, et al. Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair. J Clin Invest. 2003;112(11):1751–61.

    PubMed  CAS  Google Scholar 

  123. Park DJ, Vuong PT, de Vos S, Douer D, Koeffler HP. Comparative analysis of genes regulated by PML/RAR alpha and PLZF/RAR alpha in response to retinoic acid using oligonucleotide arrays. Blood. 2003;102(10):3727–36.

    Article  PubMed  CAS  Google Scholar 

  124. Muller-Tidow C, Steffen B, Cauvet T, Tickenbrock L, Ji P, Diederichs S, et al. Translocation products in acute myeloid leukemia activate the Wnt signaling pathway in hematopoietic cells. Mol Cell Biol. 2004;24(7):2890–904.

    Article  PubMed  CAS  Google Scholar 

  125. Perez A, Kastner P, Sethi S, Lutz Y, Reibel C, Chambon P. PMLRAR homodimers: distinct DNA binding properties and heterodimeric interactions with RXR. EMBO J. 1993;12:3171–82.

    PubMed  CAS  Google Scholar 

  126. Kamashev D, Vitoux D, De The H. PML-RARA-RXR oligomers mediate retinoid and rexinoid/cAMP cross-talk in acute promyelocytic leukemia cell differentiation. J Exp Med. 2004;199(8):1163–74.

    Article  PubMed  CAS  Google Scholar 

  127. Meani N, Minardi S, Licciulli S, Gelmetti V, Coco FL, Nervi C, et al. Molecular signature of retinoic acid treatment in acute promyelocytic leukemia. Oncogene. 2005;24(20):3358–68.

    Article  PubMed  CAS  Google Scholar 

  128. Hoemme C, Peerzada A, Behre G, Wang Y, McClelland M, Nieselt K, et al. Chromatin modifications induced by PML-RARalpha repress critical targets in leukemogenesis as analyzed by ChIP-Chip. Blood. 2008;111(5):2887–95.

    Article  PubMed  CAS  Google Scholar 

  129. Martens JH, Brinkman AB, Simmer F, Francoijs KJ, Nebbioso A, Ferrara F, et al. PML-RARalpha/RXR alters the epigenetic landscape in acute promyelocytic leukemia. Cancer Cell. 2010;17(2):173–85.

    Article  PubMed  CAS  Google Scholar 

  130. Wang K, Wang P, Shi J, Zhu X, He M, Jia X, et al. PML/RARalpha targets promoter regions containing PU.1 consensus and RARE half sites in acute promyelocytic leukemia. Cancer Cell. 2010;17(2):186–97.

    Article  PubMed  CAS  Google Scholar 

  131. van Wageningen S, Breems-de Ridder MC, Nigten J, Nikoloski G, Erpelinck-Verschueren CA, Lowenberg B, et al. Gene transactivation without direct DNA binding defines a novel gain-of-function for PML-RARalpha. Blood. 2008;111(3):1634–43.

    Article  PubMed  CAS  Google Scholar 

  132. Mueller BU, Pabst T, Fos J, Petkovic V, Fey MF, Asou N, et al. ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression. Blood. 2006;107(8):3330–8.

    Article  PubMed  CAS  Google Scholar 

  133. 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(21):5806–16.

    Article  PubMed  CAS  Google Scholar 

  134. Doucas V, Brockes J, Yaniv M, de The H, Dejean A. The PML-retinoic acid receptor-a translocation converts the receptor from an inhibitor to a retinoic acid-dependent activator of transcription factor AP-1. Proc Natl Acad Sci USA. 1993;90:9345–9.

    Article  PubMed  CAS  Google Scholar 

  135. Tussie-Luna MI, Rozo L, Roy AL. Pro-proliferative function of the long isoform of PML-RARalpha involved in acute promyelocytic leukemia. Oncogene. 2006;25(24):3375–86.

    Article  PubMed  CAS  Google Scholar 

  136. Yuan W, Payton JE, Holt MS, Link DC, Watson MA, DiPersio JF, et al. Commonly dysregulated genes in murine APL cells. Blood. 2007;109(3):961–70.

    Article  PubMed  CAS  Google Scholar 

  137. Chang LW, Payton JE, Yuan W, Ley TJ, Nagarajan R, Stormo GD. Computational identification of the normal and perturbed genetic networks involved in myeloid differentiation and acute promyelocytic leukemia. Genome Biol. 2008;9(2):R38.

    Article  PubMed  CAS  Google Scholar 

  138. Wethkamp N, Klempnauer KH. Daxx is a transcriptional repressor of CCAAT/enhancer-binding protein beta. J Biol Chem. 2009;284(42):28783–94.

    Article  PubMed  CAS  Google Scholar 

  139. Grimwade D, Biondi A, Mozziconacci MJ, Hagemeijer A, Berger R, Neat M, et al. Characterization of acute promyelocytic leukemia cases lacking the classic t(15;17): results of the European Working Party. Blood. 2000;96:1297–308.

    PubMed  CAS  Google Scholar 

  140. Gallagher RE, Mak S, Paietta E, Cooper B, Ehmann C, MS. T. Identification of a second acute promyelocytic leukemia (APL) patient with the STAT-RARa fusion gene among PML-RARa-negative Eastern Cooperative Oncology Group (ECOG) APL protocol registrants. Blood 2004; 104:821a.

    Google Scholar 

  141. Petti MC, Fazi F, Gentile M, Diverio D, De Faritiis P, De Propris MS, et al. Complete remission through blast cell differentiation in PLZF/RARa-positive acute promyelocytic leukemia: in vitro and in vivo studies. Blood. 2002;100:1065–7.

    Article  PubMed  CAS  Google Scholar 

  142. Sainty D, Liso V, Cantu-Rajnoldi A, Head D, Mozziconacci MJ, Arnoulet C, et al. A new morphologic classification system for acute promyelocytic leukemia distinguishes cases with underlying PLZF/RARA gene rearrangements. Group Francais de Cytogenetique Hematologique, UK Cancer Cytogenetics Group and BIOMED 1 European Coomunity-Concerted Acion “Molecular Cytogenetic Diagnosis in Haematological Malignancies. Blood. 2000;96(4):1287–96.

    PubMed  CAS  Google Scholar 

  143. Koken MH, Daniel MT, Gianni M, Zelent A, Licht J, Buzyn A, et al. Retinoic acid, but not arsenic trioxide, degrades the PLZF/RARalpha fusion protein, without inducing terminal differentiation or apoptosis, in a RA-therapy resistant t(11;17)(q23;q21) APL patient. Oncogene. 1999;18(4):1113–8.

    Article  PubMed  CAS  Google Scholar 

  144. Rego EM, He LZ, Warrell Jr RP, Wang ZG, Pandolfi PP. 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 USA. 2000;97:10173–8.

    Article  PubMed  CAS  Google Scholar 

  145. Rice KL, Hormaeche I, Doulatov S, Flatow JM, Grimwade D, Mills KI, et al. Comprehensive genomic screens identify a role for PLZF-RARalpha as a positive regulator of cell proliferation via direct regulation of c-MYC. Blood. 2009;114(27):5499–511.

    Article  PubMed  CAS  Google Scholar 

  146. He LZ, Guidez F, Tribioli C, Peruzzi D, Ruthardt M, Zelent A, et al. Distinct interactions of PML-RARa and PLZF-RARa with co-repressors determine differential responses to RA in APL. Nat Genet. 1998;18:126–34.

    Article  PubMed  CAS  Google Scholar 

  147. Licht J, Chomienne C, Goy A, Chen A, Scott A, Head D, et al. Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17). Blood. 1995;85:1083–94.

    PubMed  CAS  Google Scholar 

  148. Yeyati PL, Shaknovich R, Boterashvili S, Li J, Ball HJ, Waxman S, et al. Leukemia translocation protein PLZF inhibits cell growth and expression of cyclin A. Oncogene. 1999;18:925.

    Article  PubMed  CAS  Google Scholar 

  149. Guidez F, Parks S, Wong H, Jovanovic JV, Mays A, Gilkes AF, et al. RARalpha-PLZF overcomes PLZF-mediated repression of CRABPI, contributing to retinoid resistance in t(11;17) acute promyelocytic leukemia. Proc Natl Acad Sci USA. 2007;104(47):18694–9.

    Article  PubMed  CAS  Google Scholar 

  150. Buijs A, Bruin M. Fusion of FIP1L1 and RARA as a result of a novel t(4;17)(q12;q21) in a case of juvenile myelomonocytic leukemia. Leukemia. 2007;21(5):1104–8.

    PubMed  CAS  Google Scholar 

  151. Cools J, Stover EH, Wlodarska I, Marynen P, Gilliland DG. The FIP1L1-PDGFRalpha kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia. Curr Opin Hematol. 2004;11(1):51–7.

    Article  PubMed  CAS  Google Scholar 

  152. Redner RL, Rush EA, Faas S, Rudert WA, Corey SJ. The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin-retinoic acid receptor form. Blood. 1996;87:882–6.

    PubMed  CAS  Google Scholar 

  153. Wells RA, Hummel JL, De Koven A, Zipursky A, Kirby M, Dube I, et al. A new variant translocation in acute promyelocytic leukaemia: molecular characterization and clinical consideration. Leukemia. 1996;10:735–40.

    PubMed  CAS  Google Scholar 

  154. Kusakabe M, Suzukawa K, Nanmoku T, Obara N, Okoshi Y, Mukai HY, et al. Detection of the STAT5B-RARA fusion transcript in acute promyelocytic leukemia with the normal chromosome 17 on G-banding. Eur J Haematol. 2008;80(5):444–7.

    Article  PubMed  CAS  Google Scholar 

  155. Redner RL, Corey SL, Rush EA. Differentiation of t(5;17) variant acute promyelocytic leukemic blasts by all-trans retinoic acid. Leukemia. 1997;11:1014–6.

    Article  PubMed  CAS  Google Scholar 

  156. Okazuka K, Masuko M, Seki Y, Hama H, Honma N, Furukawa T, et al. Successful all-trans retinoic acid treatment of acute promyelocytic leukemia in a patient with NPM/RAR fusion. Int J Hematol. 2007;86(3):246–9.

    Article  PubMed  CAS  Google Scholar 

  157. Rego EM, Ruggero D, Tribioli C, Cattoretti G, Kogan S, Redner RL, et al. Leukemia with distinct phenotypes in transgenic mice expressing PML/RAR alpha, PLZF/RAR alpha or NPM/RAR alpha. Oncogene. 2006;25(13):1974–9.

    Article  PubMed  CAS  Google Scholar 

  158. Chen Y, Gu L, Zhou C, Wu X, Gao J, Li Q, et al. Relapsed APL patient with variant NPM-RARalpha fusion responded to arsenic trioxide-based therapy and achieved long-term survival. Int J Hematol. 2010;91(4):708–10.

    Article  PubMed  Google Scholar 

  159. Lafage-Pochitaloff M, Alcalay M, Brunel V, Longo L, Sainty D, Simonetti J, et al. Acute promyelocytic leukemia cases with nonreciprocal PML/RARa or RARa/PML fusion genes. Blood. 1995;85(5):1169–74.

    PubMed  CAS  Google Scholar 

  160. Raelson JV, Nervi C, Rosenauer A, Benedetti L, Monczak Y, Pearson M, et al. The PML/RARa oncoprotein is a direct molecular target of retinoic acid in acute promyelocytic leukemia cells. Blood. 1996;88:2826–32.

    PubMed  CAS  Google Scholar 

  161. Zhu J, Koken MHM, Quignon F, Chelbi-Alix MK, Degos L, Wang ZY, et al. Arsenic-induced PML targeting onto nuclear bodies: implications for the treatment of acute promyelocytic leukemia. Proc Natl Acad Sci USA. 1997;94:3978–83.

    Article  PubMed  CAS  Google Scholar 

  162. Tamayo P, Slonim D, Mesirov J, Zhu Q, Kitareewan S, Dmitrovsky E, et al. Interpreting patterns of gene expression with self-organizing maps: methods and application to hematopoietic differentiation. Proc Natl Acad Sci USA. 1999;96:2907–12.

    Article  PubMed  CAS  Google Scholar 

  163. Liu T-X, Zhang J-W, Tao J, Zhang R-B, Zhang Q-H, Zhao C-J, et al. Gene expression networks underlying retinoic acid-induced differentiation of acute promyelocytic leukemia cells. Blood. 2000;96:1496–504.

    PubMed  CAS  Google Scholar 

  164. 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;6:680–6.

    Article  CAS  Google Scholar 

  165. Park DJ, Chumakov AM, Vuong PT, Chih DY, Gombart AF, Miller Jr WH, et al. CCAAT/enhancer binding protein e is a potential retinoid target gene in acute promyelocytic leukemia treatment. J Clin Invest. 1999;103:1399–408.

    Article  PubMed  CAS  Google Scholar 

  166. Zheng PZ, Wang KK, Zhang QY, Huang QH, Du YZ, Zhang QH, 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. 2005;102(21):7653–8.

    Article  PubMed  CAS  Google Scholar 

  167. Imaizumi M, Suzuki H, Yoshinari M, Sato A, Saito T, Sugawara A, et al. Mutations in the E-domain of RARa portion of the PML/RARa chimeric gene may confer clinical resistance to all-trans retinoic acid in acute promyelocytic leukemia. Blood. 1998;92:374–82.

    PubMed  CAS  Google Scholar 

  168. Ding W, Li YP, Nobile LM, Grills G, Carrera I, Paietta E, et al. Leukemic cellular retinoic acid resistance and missense mutations in the PML-RARa fusion gene after relapse of acute promyelocytic leukemia from treatment with all-trans retinoic acid and intensive chemotherapy. Blood. 1998;92:1172–83.

    PubMed  CAS  Google Scholar 

  169. Gallagher RE. Retinoic acid resistance in acute promyelocytic leukemia. Leukemia. 2002;16:1940–58.

    Article  PubMed  CAS  Google Scholar 

  170. Truong BT, Lee YJ, Lodie TA, Park DJ, Perrotti D, Watanabe N, et al. CCAAT/Enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia. Blood. 2003;101(3):1141–8.

    Article  PubMed  CAS  Google Scholar 

  171. Yoshida H, Ichikawa H, Tagata Y, Katsumoto T, Ohnishi K, Akao Y, et al. PML-retinoic acid receptor alpha inhibits PML IV enhancement of PU.1-induced C/EBPepsilon expression in myeloid differentiation. Mol Cell Biol. 2007;27(16):5819–34.

    Article  PubMed  CAS  Google Scholar 

  172. Jing Y, Dai J, Chalmers-Redman RME, Tatton WG, Waxman S. Arsenic trioxide selectively induces acute promyelocytic leukemia cell apoptosis via a hydrogen peroxide-dependent pathway. Blood. 1999;94:2102–11.

    PubMed  CAS  Google Scholar 

  173. Nervi C, Ferrara FF, Fanelli M, Tippo MP, Tomassini B, Ferrucci PF, et al. Caspases mediate retinoic acid-induced degradation of the acute promyelocytic leukemia PML/RARa fusion protein. Blood. 1998;92:2244–51.

    PubMed  CAS  Google Scholar 

  174. Shah SJ, Blumen S, Pitha-Rowe I, Kitareewan S, Freemantle SJ, Feng Q, et al. UBE1L represses PML/RAR{alpha} by targeting the PML domain for ISG15ylation. Mol Cancer Ther. 2008;7(4):905–14.

    Article  PubMed  CAS  Google Scholar 

  175. Harris MN, Ozpolat B, Abdi F, Gu S, Legler A, Mawuenyega KG, et al. Comparative proteomic analysis of all-trans-retinoic acid treatment reveals systematic posttranscriptional control mechanisms in acute promyelocytic leukemia. Blood. 2004;104(5):1314–23.

    Article  PubMed  CAS  Google Scholar 

  176. Hattori H, Zhang X, Jia Y, Subramanian KK, Jo H, Loison F, et al. RNAi screen identifies UBE2D3 as a mediator of all-trans retinoic acid-induced cell growth arrest in human acute promyelocytic NB4 cells. Blood. 2007;110(2):640–50.

    Article  PubMed  CAS  Google Scholar 

  177. Ozpolat B, Akar U, Steiner M, Zorrilla-Calancha I, Tirado-Gomez M, Colburn N, et al. Programmed cell death-4 tumor suppressor protein contributes to retinoic acid-induced terminal granulocytic differentiation of human myeloid leukemia cells. Mol Cancer Res. 2007;5(1):95–108.

    Article  PubMed  CAS  Google Scholar 

  178. Kannan-Thulasiraman P, Dolniak B, Kaur S, Sassano A, Kalvakolanu DV, Hay N, et al. Role of the translational repressor 4E-BP1 in the regulation of p21(Waf1/Cip1) expression by retinoids. Biochem Biophys Res Commun. 2008;368(4):983–9.

    Article  PubMed  CAS  Google Scholar 

  179. Witcher M, Ross DT, Rousseau C, Deluca L, Miller Jr WH. Synergy between all-trans retinoic acid and tumor necrosis factor pathways in acute leukemia cells. Blood. 2003;102(1):237–45.

    Article  PubMed  CAS  Google Scholar 

  180. Miller Jr WH, Schipper HM, Lee JS, Singer J, Waxman S. Mechanisms of action of arsenic trioxide. Cancer Res. 2002;62(14):3893–903.

    PubMed  CAS  Google Scholar 

  181. Sumi D, Shinkai Y, Kumagai Y. Signal transduction pathways and transcription factors triggered by arsenic trioxide in leukemia cells. Toxicol Appl Pharmacol. 2010;244(3):385–92.

    Article  PubMed  CAS  Google Scholar 

  182. Cai X, Shen YL, Zhu Q, Jia PM, Yu Y, Zhou L, et al. Arsenic trioxide-induced apoptosis and differentiation are associated respectively with mitochondrial transmembrane potential collapse and retinoic acid signaling pathways in acute promyelocytic leukemia. Leukemia. 2000;14:262–70.

    Article  PubMed  CAS  Google Scholar 

  183. Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997;89:3354–60.

    PubMed  CAS  Google Scholar 

  184. Fujisawa S, Ohno R, Shigeno K, Sahara N, Nakamura S, Naito K, et al. Pharmacokinetics of arsenic species in Japanese patients with relapsed or refractory acute promyelocytic leukemia treated with arsenic trioxide. Cancer Chemother Pharmacol. 2007;59(4):485–93.

    Article  PubMed  CAS  Google Scholar 

  185. Fox E, Razzouk BI, Widemann BC, Xiao S, O’Brien M, Goodspeed W, et al. Phase 1 trial and pharmacokinetic study of arsenic trioxide in children and adolescents with refractory or relapsed acute leukemia, including acute promyelocytic leukemia or lymphoma. Blood. 2008;111(2):566–73.

    Article  PubMed  CAS  Google Scholar 

  186. Chen G-Q, Zhou L, Styblo M, Walton F, Jing Y, Weinberg R, et al. Methylated metabolites of arsenic trioxide are more potent than arsenic trioxide as apoptotic but not differentiation inducers in leukemia and lymphoma cells. Cancer Res. 2003;63:1853–9.

    PubMed  CAS  Google Scholar 

  187. Yoshino Y, Yuan B, Miyashita SI, Iriyama N, Horikoshi A, Shikino O, et al. Speciation of arsenic trioxide metabolites in blood cells and plasma of a patient with acute promyelocytic leukemia. Anal Bioanal Chem. 2009;393(2):689–97.

    Article  PubMed  CAS  Google Scholar 

  188. Soignet SL, Maslak P, Wang ZG, Jhanwar S, Calleja E, Dardashti LJ, et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Eng J Med. 1998;339:1341–8.

    Article  CAS  Google Scholar 

  189. Sternsdorf T, Puccetti E, Jensen K, Hoelzer D, Will H, Ottmann OG, et al. PIC-1/SUMO-1 modified PML-retinoic acid receptor a mediates arsenic trioxide-induced apoptosis in acute promyelocytic leukemia. Mol Cell Biol. 1999;19:5170–8.

    PubMed  CAS  Google Scholar 

  190. Lallemand-Breitenbach V, Zhu J, Puvion F, Koken M, Honore N, Doubeikovsky A, et al. Role of promyelocytic leukemia (PML) sumolation in nuclear body formation, 11S proteasome recruitment, and As2O3-induced PML or PML/retinoic acid receptor alpha degradation. J Exp Med. 2001;193(12):1361–71.

    Article  PubMed  CAS  Google Scholar 

  191. Zhang XW, Yan XJ, Zhou ZR, Yang FF, Wu ZY, Sun HB, et al. Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML. Science. 2010;328(5975):240–3.

    Article  PubMed  CAS  Google Scholar 

  192. 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(21):7172–82.

    Article  PubMed  CAS  Google Scholar 

  193. Lunghi P, Tabilio A, Lo-Coco F, Pelicci PG, Bonati A. Arsenic trioxide (ATO) and MEK1 inhibition synergize to induce apoptosis in acute promyelocytic leukemia cells. Leukemia. 2005;19(2):234–44.

    Article  PubMed  CAS  Google Scholar 

  194. Zhu X-H, Shen Y-L, Y-k J, Cai X, Jia P-M, Huang Y, et al. Apoptosis and growth inhibition in malignant lymphocytes after treatment with arsenic trioxide at clinically achievable concentrations. J Natl Cancer Inst. 1999;91:772–8.

    Article  PubMed  CAS  Google Scholar 

  195. Davison K, Cote S, Mader S, Miller WH. Glutathione depletion overcomes resistance to arsenic trioxide in arsenic-resistant cell lines. Leukemia. 2003;17(5):931–40.

    Article  PubMed  CAS  Google Scholar 

  196. Li L, Wang J, Ye RD, Shi G, Jin H, Tang X, et al. PML/RARalpha fusion protein mediates the unique sensitivity to arsenic cytotoxicity in acute promyelocytic leukemia cells: Mechanisms involve the impairment of cAMP signaling and the aberrant regulation of NADPH oxidase. J Cell Physiol. 2008;217(2):486–93.

    Article  PubMed  CAS  Google Scholar 

  197. Gianni M, Koken MHM, Chelbi-Alix MK, Benoit G, Lanotte M, Chen Z, et al. Combined arsenic and retinoic acid treatment enhances differentiation and apoptosis in arsenic-resistant NB4 cells. Blood. 1998;91:4300–10.

    PubMed  CAS  Google Scholar 

  198. Sen CK. Redox signaling and the emerging therapeutic potential of thiol antioxidants. Biochem Pharmacol. 1998;55(11):1747–58.

    Article  PubMed  CAS  Google Scholar 

  199. Dai J, Weinberg RS, Waxman S, Jing Y. Malignant cell can be sensitized to undergo growth inhibition and apoptosis by arsenic trioxide through modulation of the glutathione redox system. Blood. 1999;93:268–77.

    PubMed  CAS  Google Scholar 

  200. Lu J, Chew EH, Holmgren A. Targeting thioredoxin reductase is a basis for cancer therapy by arsenic trioxide. Proc Natl Acad Sci USA. 2007;104(30):12288–93.

    Article  PubMed  CAS  Google Scholar 

  201. 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(13):4578–83.

    Article  PubMed  CAS  Google Scholar 

  202. Wang J, Li L, Cang H, Shi G, Yi J. NADPH oxidase-derived reactive oxygen species are responsible for the high susceptibility to arsenic cytotoxicity in acute promyelocytic leukemia cells. Leuk Res. 2008;32(3):429–36.

    Article  PubMed  CAS  Google Scholar 

  203. Lin P, Welch EJ, Gao XP, Malik AB, Ye RD. Lysophosphatidylcholine modulates neutrophil oxidant production through elevation of cyclic AMP. J Immunol. 2005;174(5):2981–9.

    PubMed  CAS  Google Scholar 

  204. Davison K, Mann KK, Waxman S, Miller Jr WH. JNK activation is a mediator of arsenic trioxide-induced apoptosis in acute promyelocytic leukemia cells. Blood. 2004;103(9):3496–502.

    Article  PubMed  CAS  Google Scholar 

  205. Bernardini S, Nuccetelli M, Noguera NI, Bellincampi L, Lunghi P, Bonati A, et al. Role of GSTP1-1 in mediating the effect of As2O3 in the acute promyelocytic leukemia cell line NB4. Ann Hematol. 2006;85(10):681–7.

    Article  PubMed  CAS  Google Scholar 

  206. Chou WC, Chen HY, Yu SL, Cheng L, Yang PC, Dang CV. Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005;106(1):304–10.

    Article  PubMed  CAS  Google Scholar 

  207. Shao W, Fanelli M, Ferrara FF, Riccioni R, Rosenauer A, Davison K, et al. As2O3 induced apoptosis and loss of PML/RARa protein in both retinoid sensitive and resistant APL cells. J Natl Cancer Inst. 1998;90:124–33.

    Article  PubMed  CAS  Google Scholar 

  208. Jing Y, Wang L, Xia L, Chen G-Q, Chen Z, Miller Jr WH, et al. Combined effect of all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia cells in vitro and in vivo. Blood. 2001;97:264–9.

    Article  PubMed  CAS  Google Scholar 

  209. Sun Y, Kim SH, Zhou DC, Ding W, Paietta E, Guidez F, et al. Acute promyeloctyic leukemia cell line AP-1060 established as a cytokine-dependent culture from a patient clinically-resistant to all-trans retinoic acid and arsenic trioxide. Leukemia. 2004;18:1258–69.

    Article  PubMed  CAS  Google Scholar 

  210. Lallemand-Breitenbach V, Guillemin MC, Janin A, Daniel MT, Degos L, Kogan SC, et al. Retinoic acid and arsenic synergize to eradicate leukemic cells in a mouse model of acute promyelocytic leukemia. J Exp Med. 1999;189:1043–52.

    Article  PubMed  CAS  Google Scholar 

  211. Westervelt P, Pollock JL, Oldfather KM, Walter MJ, Ma MK, Williams A, et al. Adaptive immunity cooperates with liposomal all-trans-retinoic acid (ATRA) to facilitate long-term molecular remissions in mice with acute promyelocytic leukemia. Proc Natl Acad Sci USA. 2002;99(14):9468–73.

    Article  PubMed  CAS  Google Scholar 

  212. Grimwade D, Enver T. Acute promyelocytic leukemia: where does it stem from? Leukemia. 2004;18(3):375–84.

    Article  PubMed  CAS  Google Scholar 

  213. Zheng X, Seshire A, Ruster B, Bug G, Beissert T, Puccetti E, et al. Arsenic but not all-trans retinoic acid overcomes the aberrant stem cell capacity of PML/RARa-positive leukemic stem cells. Haematologica. 2007;92:323–31.

    Article  PubMed  CAS  Google Scholar 

  214. Bonomi R, Giordano H, del Pilar Moreno M, Bodega E, Gallagher R, et al. Simultaneous PML/RARalpha and AML1/ETO expression with t(15;17) at onset and relapse with only t(8;21) in an acute promyelocytic leukemia patient. Cancer Genet Cytogenet. 2000;123(1):41–3.

    Article  PubMed  CAS  Google Scholar 

  215. Gurrieri C, Nafa K, Merghoub T, Bernardi R, Capodieci P, Biondi A, et al. Mutations of the PML tumor suppressor gene in acute promyelocytic leukemia. Blood. 2004;103(6):2358–62.

    Article  PubMed  CAS  Google Scholar 

  216. Chen Z-X, Xue Y-Q, Zhang R, Tao R-F, Xia X-M, Li C, et al. A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukemia patients. Blood. 1991;78:1413–9.

    PubMed  CAS  Google Scholar 

  217. Frankel SR, Eardley A, Heller G, Berman E, Miller Jr WH, Dmitrovsky E, et al. All-trans-retinoic acid for acute promyelocytic leukemia: results of the New York study. Ann Int Med. 1994;120:278–86.

    PubMed  CAS  Google Scholar 

  218. Warrell Jr RP. Retinoid resistance in acute promyelocytic leukemia: new mechanisms, strategies and implications. Blood. 1993;82:1949–53.

    PubMed  CAS  Google Scholar 

  219. Muindi J, Frankel S, Miller Jr WH, Jakubowski A, Scheinberg D, Young C, 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. 1992;79:299–303.

    PubMed  CAS  Google Scholar 

  220. Adamson PC, Bailey J, Pluda J, Poplack DG, Bauza S, Murphy RF, et al. Pharmacokinetics of all-trans-retinoic acid administered on an intermittent schedule. J Clin Oncol. 1995;13(4):1238–41.

    PubMed  CAS  Google Scholar 

  221. Miller Jr WH, Jakubowski A, Tong WP, Miller VA, Rigas JR, Benedetti F, et al. 9-cis retinoic acid induces complete remission but does not reverse clinically acquired retinoid resistance in acute promyelocytic leukemia. Blood. 1995;85:3021–7.

    PubMed  CAS  Google Scholar 

  222. Tobita T, Takeshita A, Kitamura K, Ohnishi K, Yanagi M, Hiraoka A, et al. Treatment with a new synthetic retinoid, Am80, of acute promyelocytic leukemia relapsed from complete remission induced by all-trans retinoic acid. Blood. 1997;90:967–73.

    PubMed  CAS  Google Scholar 

  223. Douer D, Estey E, Santillana S, Bennett JM, Lopez-Berestein G, Boehm K, et al. Treatment of newly diagnosed and relapsed acute promyelocytic leukemia with intravenous liposomal all-trans retinoic acid. Blood. 2001;97:73–80.

    Article  PubMed  CAS  Google Scholar 

  224. Cote S, Rosenauer A, Bianchini A, Seiter K, Vandewiele J, Nervi C, et al. Response to histone deacetylase inhibition of novel PML/RARalpha mutant detected in retinoic acid-resistant APL cells. Blood. 2002;100:261–70.

    Article  CAS  Google Scholar 

  225. Gallagher RE, Schachter-Tokarz EL, Zhou D-C, Ding W, Kim SH, Bi W, et al. Relapse of acute promyelocytic leukemia with PML-RARa mutant subclones independent of proximate all-trans retinoic acid selection pressure. Leukemia. 2006;20:556–62.

    Article  PubMed  CAS  Google Scholar 

  226. Schachter-Tokarz E, Kelaidi C, Cassinat B, Chomienne C, Gardin C, Raffoux E, et al. PML-RARalpha ligand-binding domain deletion mutations associated with reduced disease control and outcome after first relapse of APL. Leukemia. 2010;24:473–6.

    Article  PubMed  CAS  Google Scholar 

  227. Zhou D-C, Kim S, Ding W, Schulz C, Warrell Jr RP, Gallagher RE. Frequent mutations in the ligand binding domain of PML-RARa 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;99:1356–63.

    Article  PubMed  CAS  Google Scholar 

  228. Cote S, Zhou D, Bianchini A, Nervi C, Gallagher RE, Miller Jr WH. Altered ligand binding and transcriptional regulation by mutations in the PML/RARa ligand-binding domain arising in retinoic acid-resistant patients with acute promyelocytic leukemia. Blood. 2000;96:3200–8.

    PubMed  CAS  Google Scholar 

  229. Cornic M, Delva L, Guidez F, Balitrand N, Degos L, Chomienne C. Induction of retinoic acid-binding protein in normal and malignant human myeloid cells by retinoic acid in acute promyelocytic leukemia patients. Cancer Res. 1992;52:3329–34.

    PubMed  CAS  Google Scholar 

  230. Zhou D-C, Hallam SJ, Klein RS, Wiernik PH, Tallman MS, Gallagher RE. Constitutive expression of cellular retinoic acid binding protein II and lack of correlation with sensitivity to all-trans retinoic acid in acute promyelocytic leukemia cells. Cancer Res. 1998;58:5770–6.

    PubMed  CAS  Google Scholar 

  231. Napoli J. Retinoic acid biosynthesis and metabolism. FASEB J. 1996;10:993–1001.

    PubMed  CAS  Google Scholar 

  232. Dong D, Ruuska SE, Levinthal DJ, Noy N. Distinct roles for cellular retinoic acid-binding proteins I and II in regulating signaling by retinoic acid. J Biol Chem. 1999;274:23695–8.

    Article  PubMed  CAS  Google Scholar 

  233. Delva L, Bastie J-N, Rochette-Egly C, Kraiba R, Balitrand N, Despauy G, et al. Physical and functional interactions between cellular retinoic acid binding protein II and the retinoic acid-dependent nuclear complex. Mol Cell Biol. 1999;19:7158–67.

    PubMed  CAS  Google Scholar 

  234. Quere R, Baudet A, Cassinat B, Bertrand G, Marti J, Manchon L, et al. Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007;109(10):4450–60.

    Article  PubMed  CAS  Google Scholar 

  235. Fanelli M, Minucci S, Gelmetti V, Nervi C, Gambacorti-Passerini C, Pelicci PG. Constitutive degradation of PML/RARa through the proteasome pathway mediates retinoic acid resistance. Blood. 1999;93:1477–81.

    PubMed  CAS  Google Scholar 

  236. McNamara S, Wang H, Hanna N, Miller Jr WH. Topoisomerase IIbeta negatively modulates retinoic acid receptor alpha function: a novel mechanism of retinoic acid resistance. Mol Cell Biol. 2008;28(6):2066–77.

    Article  PubMed  CAS  Google Scholar 

  237. McNamara S, Nichol JN, Wang H, Miller Jr WH. Targeting PKC delta-mediated topoisomerase II beta overexpression subverts the differentiation block in a retinoic acid-resistant APL cell line. Leukemia. 2010;24(4):729–39.

    Article  PubMed  CAS  Google Scholar 

  238. Kambhampati S, Li Y, Verma A, Sassano A, Majchrzak B, Deb DK, et al. Activation of protein kinase C delta by all-trans-retinoic acid. J Biol Chem. 2003;278(35):32544–51.

    Article  PubMed  CAS  Google Scholar 

  239. Alsayed Y, Uddin S, Mahmud N, Lekmine F, Kalvakolanu DV, Minucci S, et al. Activation of Rac1 and the p38 mitogen-activated protein kinase pathway in response to all-trans-retinoic acid. J Biol Chem. 2001;276(6):4012–9.

    Article  PubMed  CAS  Google Scholar 

  240. Ohnuma-Ishikawa K, Morio T, Yamada T, Sugawara Y, Ono M, Nagasawa M, et al. Knockdown of XAB2 enhances all-trans retinoic acid-induced cellular differentiation in all-trans retinoic acid-­sensitive and -resistant cancer cells. Cancer Res. 2007;67(3):1019–29.

    Article  PubMed  CAS  Google Scholar 

  241. Zhao HL, Ueki N, Marcelain K, Hayman MJ. The Ski protein can inhibit ligand induced RARalpha and HDAC3 degradation in the retinoic acid signaling pathway. Biochem Biophys Res Commun. 2009;383(1):119–24.

    Article  PubMed  CAS  Google Scholar 

  242. Neri LM, Borgatti P, Tazzari PL, Bortul R, Cappellini A, Tabellini G, et al. The phosphoinositide 3-kinase/AKT1 pathway involvement in drug and all-trans-retinoic acid resistance of leukemia cells. Mol Cancer Res. 2003;1(3):234–46.

    PubMed  CAS  Google Scholar 

  243. Srinivas H, Xia D, Moore NL, Uray IP, Kim H, Ma L, et al. Akt phosphorylates and suppresses the transactivation of retinoic acid receptor alpha. Biochem J. 2006;395(3):653–62.

    Article  PubMed  CAS  Google Scholar 

  244. Ghavamzadeh A, Alimoghaddam K, Ghaffari SH, Rostami S, Jahani M, Hosseini R, et al. Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy. Ann Oncol. 2006;17(1):131–4.

    Article  PubMed  CAS  Google Scholar 

  245. Mathews V, George B, Chendamarai E, Lakshmi KM, Desire S, Balasubramanian P, et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J Clin Oncol. 2010;28(24):3866–71.

    Article  PubMed  CAS  Google Scholar 

  246. Zhou J, Zhang Y, Li J, Li X, Hou J, Zhao Y, et al. Single-agent arsenic trioxide in the treatment of children with newly diagnosed acute promyelocytic leukemia. Blood. 2010;115(9):1697–702.

    Article  PubMed  CAS  Google Scholar 

  247. Ghaffari SH, Rostami S, Bashash D, Alimoghaddam K, Ghavamzadeh A. Real-time PCR analysis of PML-RAR alpha in newly diagnosed acute promyelocytic leukaemia patients treated with arsenic trioxide as a front-line therapy. Ann Oncol. 2006;17(10):1553–9.

    Article  PubMed  CAS  Google Scholar 

  248. Ghaffari SH, Shayan-Asl N, Jamialahmadi AH, Alimoghaddam K, Ghavamzadeh A. Telomerase activity and telomere length in patients with acute promyelocytic leukemia: indicative of proliferative activity, disease progression, and overall survival. Ann Oncol. 2008;19(11):1927–34.

    Article  PubMed  CAS  Google Scholar 

  249. Thirugnanam R, George B, Chendamarai E, Lakshmi KM, Balasubramanian P, Viswabandya A, et al. Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen. Biol Blood Marrow Transplant. 2009;15(11):1479–84.

    Article  PubMed  CAS  Google Scholar 

  250. Diaz Z, Mann KK, Marcoux S, Kourelis M, Colombo M, Komarnitsky PB, et al. A novel arsenical has antitumor activity toward As2O3-resistant and MRP1/ABCC1-overexpressing cell lines. Leukemia. 2008;22(10):1853–63.

    Article  PubMed  CAS  Google Scholar 

  251. Tabellini G, Tazzari PL, Bortul R, Evangelisti C, Billi AM, Grafone T, et al. Phosphoinositide 3-kinase/Akt inhibition increases arsenic trioxide-induced apoptosis of acute promyelocytic and T-cell leukaemias. Br J Haematol. 2005;130(5):716–25.

    Article  PubMed  CAS  Google Scholar 

  252. Ramos AM, Fernandez C, Amran D, Sancho P, de Blas E, Aller P. Pharmacologic inhibitors of PI3K/Akt potentiate the apoptotic action of the antileukemic drug arsenic trioxide via glutathione depletion and increased peroxide accumulation in myeloid leukemia cells. Blood. 2005;105(10):4013–20.

    Article  PubMed  CAS  Google Scholar 

  253. 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(2):740–6.

    Article  PubMed  CAS  Google Scholar 

  254. Dilda PJ, Perrone GG, Philp A, Lock RB, Dawes IW, Hogg PJ. Insight into the selectivity of arsenic trioxide for acute promyelocytic leukemia cells by characterizing Saccharomyces cerevisiae deletion strains that are sensitive or resistant to the metalloid. Int J Biochem Cell Biol. 2008;40:1016–29.

    Article  PubMed  CAS  Google Scholar 

  255. Zhou P, Kalakonda N, Comenzo RL. Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): possible mechanisms to explain ATO resistance in vivo. Br J Haematol. 2005;128(5):636–44.

    Article  PubMed  CAS  Google Scholar 

  256. Thorsen M, Di Y, Tangemo C, Morillas M, Ahmadpour D, Van der Does C, et al. The MAPK Hog1p modulates Fps1p-dependent arsenite uptake and tolerance in yeast. Mol Biol Cell. 2006;17(10):4400–10.

    Article  PubMed  CAS  Google Scholar 

  257. Maciaszczyk-Dziubinska E, Migdal I, Migocka M, Bocer T, Wysocki R. The yeast aquaglyceroporin Fps1p is a bidirectional arsenite channel. FEBS Lett. 2010;584(4):726–32.

    Article  PubMed  CAS  Google Scholar 

  258. Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009;113(9):1875–91.

    Article  PubMed  CAS  Google Scholar 

  259. Falini B, Flenghi L, Fagioli M, Lo Coco F, Cordone I, Diverio D, et al. Immunocytochemical diagnosis of acute promyelocytic leukemia (M3) with the monoclonal antibody PG-M3 (anti-PML). Blood. 1997;90(10):4046–53.

    PubMed  CAS  Google Scholar 

  260. Paietta E, Goloubeva O, Neuberg D, Bennett JM, Gallagher RE, Racevskis J, et al. A surrogate marker profile for PML-RARa-expressing acute promyelocytic leukemia and the association of immunophenotypic markers with morphologic and molecular subtypes. Cytometry B Clin Cytom. 2004;59:1–9.

    Article  PubMed  CAS  Google Scholar 

  261. Gallagher RE, Li Y-P, Rao S, Paietta E, Andersen J, Etkind P, et al. Characterization of acute promyelocytic leukemia cases with PML-RARa break/fusion sites in PML exon 6: Identification of a subgroup with decreased in vitro responsiveness to all-trans-retinoic acid. Blood. 1995;86:1540–7.

    PubMed  CAS  Google Scholar 

  262. Callens C, Chevret S, Cayuela JM, Cassinat B, Raffoux E, de Botton S, et al. Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): a retrospective study from the European APL Group. Leukemia. 2005;19(7):1153–60.

    Article  PubMed  CAS  Google Scholar 

  263. Gonzalez M, Barragan E, Bolufer P, Chillon C, Colomer D, Borstein R, et al. Pretreatment characteristics and clinical outcome of acute promyelocytic leukaemia patients according to the PML-RARa isoforms: a study of the PETHEMA group. Br J Haematol. 2001;114:99–103.

    Article  PubMed  CAS  Google Scholar 

  264. Kuchenbauer F, Schoch C, Kern W, Hiddemann W, Haferlach T, Schnittger S. Impact of FLT3 mutations and promyelocytic leukaemia-breakpoint on clinical characteristics and prognosis in acute promyelocytic leukaemia. Br J Haematol. 2005;130(2):196–202.

    Article  PubMed  CAS  Google Scholar 

  265. Tallman MS, Kim HT, Montesinos P, Appelbaum FR, de la Serna J, Bennett JM, et al. Does microgranular variant morphology of acute promyelocytic leukemia independently predict for a less favorable outcome compared with classical M3 APL? A joint study of the North American Intergroup and the PETHEMA Group. Blood. 2010;116(25):5650–9.

    Article  PubMed  CAS  Google Scholar 

  266. Fukutani H, Naoe T, Ohno R, Yoshida H, Miyawaki S, Shimazaki C, et al. Prognostic significance of the RT-PCR assay of PML-RARA transcripts in acute promyelocytic leukemia. Leukemia. 1995;9:588–93.

    PubMed  CAS  Google Scholar 

  267. Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, et al. Molecular remission in PML/RARa-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Blood. 1997;90:1014–21.

    PubMed  CAS  Google Scholar 

  268. 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;93:4131–43.

    PubMed  CAS  Google Scholar 

  269. Stock W, Moser B, Powell BL, Appelbaum FR, Tallman MS, Larson RA, et al. Prognostic significance of initial clincial and molecular genetic features of actue promeylocytic leukemia (APL): Results from the North American Intergroup Trial C9710 (Abstract #7016). J Clin Oncol (Suppl) 2007;25:361s.

    Google Scholar 

  270. Chillon MC, Santamaria C, Garcia-Sanz R, Balanzategui A, Maria Eugenia S, Alcoceba M, et al. Long FLT3 internal tandem duplications and reduced PML-RARalpha expression at diagnosis characterize a high-risk subgroup of acute promyelocytic leukemia patients. Haematologica. 2010;95(5):745–51.

    Article  PubMed  CAS  Google Scholar 

  271. Cervera J, Montesinos P, Hernandez-Rivas JM, Calasanz MJ, Aventin A, Ferro MT, et al. Additional chromosome abnormalities in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Haematologica. 2010;95(3):424–31.

    Article  PubMed  CAS  Google Scholar 

  272. Schnittger S, Weisser M, Schoch C, Hiddemann W, Haferlach T, Kern W. New score predicting for prognosis in PML-RARA-, AML1-ETO-, or CBFB-MYH11-positive acute myeloid leukemia based on quantification of fusion transcripts. Blood. 2003;102:2746–55.

    Article  PubMed  CAS  Google Scholar 

  273. Gallagher RE, Yeap BY, Bi W, Livak KJ, Beaubier N, Rao S, et al. Quantitative real-time RT-PCR analysis of PML-RARa mRNA in adult acute promyelocytic leukemia: assessment of prognostic significance in adult patients from intergroup protocol 0129. Blood. 2003;101:2521–8.

    Article  PubMed  CAS  Google Scholar 

  274. Weisberg E, Sattler M, Ray A, Griffin JD. Drug resistance in mutant FLT3-positive AML. Oncogene. 2010;29(37):5120–34.

    Article  PubMed  CAS  Google Scholar 

  275. Beitinjaneh A, Jang S, Roukoz H, Majhail NS. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations in acute promyelocytic leukemia: a systematic review. Leuk Res. 2010;34(7):831–6.

    Article  PubMed  CAS  Google Scholar 

  276. Noguera N, Breccia M, Divona M, Diverio D, Costa V, Avvisati G, et al. Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol. Leukemia. 2002;16:2185–9.

    Article  PubMed  CAS  Google Scholar 

  277. Au WY, Fung A, Chim CS, Lie AK, Liang R, Ma ES, et al. FLT-3 aberrations in acute promyelocytic leukaemia: clinicopathological associations and prognostic impact. Br J Haematol. 2004;125(4):463–9.

    Article  PubMed  CAS  Google Scholar 

  278. Gale RE, Hills R, Pizzey AR, Kottaridis PD, Swirsky D, Gilkes AF, et al. Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Blood. 2005;106(12):3768–76.

    Article  PubMed  CAS  Google Scholar 

  279. Stock W, Moser B, Najib K, Powell B, Gulati K, Holowka N et al. High incidence of FLT3 mutations in adults with acute promyelocytic leukemia (APL): Correlation with diagnostic features and treatment outcome (C-9710) [abstract]. J Clin Oncol (Suppl) 2008

    Google Scholar 

  280. Whitman SP, Archer KJ, Feng L, Baldus C, Becknell B, Carlson BD, et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study. Cancer Res. 2001;61(19):7233–9.

    PubMed  CAS  Google Scholar 

  281. Santamaria C, Chillon MC, Garcia-Sanz R, Balanzategui A, Sarasquete ME, Alcoceba M, et al. The relevance of preferentially expressed antigen of melanoma (PRAME) as a marker of disease activity and prognosis in acute promyelocytic leukemia. Haematologica. 2008;93(12):1797–805.

    Article  PubMed  Google Scholar 

  282. Hu J, Liu YF, Wu CF, Xu F, Shen ZX, Zhu YM, 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. 2009;106(9):3342–7.

    Article  PubMed  CAS  Google Scholar 

  283. Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, et al. Arsenic trioxide improves event-free and over-all ­survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010;116:3751–7.

    Article  PubMed  CAS  Google Scholar 

  284. Gore SD, Gojo I, Sekeres MA, Morris L, Devetten MP, Jamieson K, et al. A single cycle of arsenic trioxide-based consolidation chemotherapy spares anthracycline exposure in the primary management of acute promyelocytic leukemia. J Clin Oncol. 2010;28:1047–53.

    Article  PubMed  CAS  Google Scholar 

  285. van Dongen JJM, Macintyre EA, Gabert JA, Delabesse E, Rossi V, Saglio G, et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Leukemia. 1999;13:1901–28.

    Article  PubMed  CAS  Google Scholar 

  286. Livak KJ, Flood SJ, Marmaro J, Giusti W, Deetz K. Oligonucleotides with fluorescent dyes at opposite ends provide a quenched probe system useful for detecting PCR product and nucleic acid hybridization. PCR Methods Appl. 1995;4(6):357–62.

    PubMed  CAS  Google Scholar 

  287. Gabert J, Beillard E, van der Velden V, Bi W, Grimwade D, Pallisgaard N. Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) of fusion gene transcripts for residual disease detection in leukemia – A Europe Against Cancer Program. Leukemia. 2003;17:2318–57.

    Article  PubMed  CAS  Google Scholar 

  288. Santamaria C, Chillon MC, Fernandez C, Martin-Jimenenz P, Balanzategui A, Sanz RG, et al. Using quantification of the PML-RARa transcript to stratify the risk of relapse in patients with acute promyelocytic leukemia. Haematologica. 2007;92:315–22.

    Article  PubMed  CAS  Google Scholar 

  289. Gallagher R, Schachter-Tokarz E, Zhou D-C, Liao K, Jones D, Estey E. MRD monitoring in acute promyelocytic leukemia: unresolved issues in 2005. Hematol Rep. 2005;1:76–9.

    Google Scholar 

  290. Diverio D, Rossi V, Avvisati G, De Santis S, Pistilli A, Pane F, et al. Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RARa fusion gene in patient with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter “AIDA” trial. Blood. 1998;92:784–9.

    PubMed  CAS  Google Scholar 

  291. Grimwade D, Lo Coco F. Acute promyelocytic leukemia: a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia. Leukemia. 2002;16:1959–73.

    Article  PubMed  CAS  Google Scholar 

  292. LoCoco F, Diverio D, Avvisati G, Petti MC, Meloni G, Pogliani EM, et al. Therapy of molecular relapse in acute promyelocytic leukemia. Blood. 1999;94:2225–9.

    CAS  Google Scholar 

  293. Esteve J, Escoda L, Martin G, Rubio V, Diaz-Mediavilla J, Gonzalez M, et al. Outcome of patients with acute promyelocytic leukemia failing to front-line treatment with all-trans retinoic acid and anthracycline-based chemotherapy (PETHEMA protocols LPA96 and LPA99): benefit of an early intervention. Leukemia. 2007;21(3):446–52.

    Article  PubMed  CAS  Google Scholar 

  294. Cassinat B, de Botton S, Kelaidi C, Ades L, Zassadowski F, Guillemot I et al. When can real-time quantitative RT-PCR effectively define molecular relapse in acute promyelocytic leukemia patients? (Results of the French Belgian Swiss APL Group). Leuk Res 2009.

    Google Scholar 

  295. Grimwade D, Jovanovic JV, Hills RK, Nugent EA, Patel Y, Flora R, et al. Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy. J Clin Oncol. 2009;27(22):3650–8.

    Article  PubMed  CAS  Google Scholar 

  296. Gallagher RE. Real-time consensus on relapse risk in acute promyelocytic leukemia. Leuk Res 2009.

    Google Scholar 

  297. Ommen HB, Schnittger S, Jovanovic JV, Ommen IB, Hasle H, Ostergaard M, et al. Strikingly different molecular relapse kinetics in NPM1c, PML-RARA, RUNX1-RUNX1T1, and CBFB-MYH11 acute myeloid leukemias. Blood. 2010;115(2):198–205.

    Article  PubMed  CAS  Google Scholar 

  298. Vickers M, Jackson G, Taylor P. The incidence of cute promyelocytic leukemia appears constant over most of a human lifespan, implying only one rate limiting mutation. Leukemia. 2000;14:722.

    Article  PubMed  CAS  Google Scholar 

  299. Carter M, Kalwinsky DK, Dahl GV, et al. Childhood acute promyelocytic leukemia: a rare variant of nonlymphoid leukemia with distinctive clinical and biologic features. Leukemia. 1989;3:298.

    PubMed  CAS  Google Scholar 

  300. Biondi A, Rovelli A, Cantù-Rajnoldi A, et al. Acute promyelocytic leukemia in children: Experience of the Italian Pediatric Hematology and Oncology Group (AIEOP). Leukemia. 1994;8 Suppl 2:S66.

    PubMed  Google Scholar 

  301. Maule MM, Damma E, Mosso ML, et al. High incidence of acute promyelocytic leukemia in children in northwest Italy, 1980–2003: a report from the childhood cancer registry of Piedmont. Leukemia. 2008;22:439–41.

    Article  PubMed  CAS  Google Scholar 

  302. Biondi A, Rovelli A, Cantŭ-Raynoldi A, et al. Acute promyelocytic leukemia in children: experience of the Italian pediatric hematology and oncology group (AIEOP). Leukemia. 1994;8:1264–8.

    PubMed  CAS  Google Scholar 

  303. Malta-Corea A, Pacheco Espinoza C, Cantù-Rajnoldi A, et al. Childhood acute promyelocytic leukemia in Nicaragua. Ann Oncol. 1993;4:892.

    PubMed  CAS  Google Scholar 

  304. Douer D, Preston-Martin S, Chang E, et al. High frequency of acute promyelocytic leukemia among Latinos with acute myeloid leukemia. Blood. 1996;87:308.

    PubMed  CAS  Google Scholar 

  305. Hernández P, Milanés MT, Svarch E, et al. High relative proportion of acute promyelocytic leukemia in children: experience of a multicenter study in Cuba. Leuk Res. 2000;24:739–40.

    Article  PubMed  Google Scholar 

  306. Matasar MJ, Ritchie EK, Consedine N, et al. Incidence rates of acute promyelocytic leukemia among Hispanics, blacks, Asians and non-Hispanic whites in the United States. Eur J Cancer Prev. 2006;15:367–70.

    Article  PubMed  Google Scholar 

  307. Wiernik PH, Andersen JW. Unpublished observations, 1994.

    Google Scholar 

  308. Mele A, Stazi MA, Pulsoni A, et al. Epidemiology of acute promyelocytic leukemia. Haematologica. 1995;80:405.

    PubMed  CAS  Google Scholar 

  309. Pulsoni A, Stazi A, Cotichini R, et al. Acute promyelocytic leukemia: Epidemiology and risk factors. A report of the GIMEMA Italian archive of adult acute leukaemia. GIMEMA Cooperative Group. Eur J Haematol. 1998;61:327.

    Article  PubMed  CAS  Google Scholar 

  310. Estey E, Thall P, Kantarjian H, et al. Association between increased body mass index and a diagnosis of acute promyelocytic leukemia in patients with acute myeloid leukemia. Leukemia. 1997;12:1503.

    Google Scholar 

  311. Jeddi R, Ghédira H, Mnif S, et al. High body mass index is an independent predictor of differentiation syndrome in patients with acute promyelocytic leukemia. Leuk Res. 2010;34:545–7.

    Article  PubMed  Google Scholar 

  312. Yin CC, Glassman AP, Lin P, et al. Morphologic, cytogenetic and molecular abnormalities in therapy-related acute promyelocytic leukemia. Am J Clin Pathol. 2005;123:840–8.

    Article  PubMed  Google Scholar 

  313. Beaumont M, Sanz M, Carli PM, et al. Therapy-related acute promyelocytic leukemia. J Clin Oncol. 2003;21:2123–37.

    Article  PubMed  CAS  Google Scholar 

  314. Au WY, Ma SK, Chung LP, et al. Two cases of therapy-related acute promyelocytic leukemia (t-APL) after mantle cell lymphoma and gestational trophoblastic disease. Ann Hematol. 2002;81:659–71.

    Article  PubMed  CAS  Google Scholar 

  315. Mays AN, Osheroff N, Xiao Y, et al. Evidence for direct involvement of epirubicin in the formation of chromosomal translocations in t(15;17) therapy-related acute promyelocytic leukemia. Blood. 2010;115:326–30.

    Article  PubMed  CAS  Google Scholar 

  316. Mistry AR, Felix CA, Whitmarch RJ, et al. DNA topoisomerase II in therapy-related acute promyelocytic leukemia. N Engl J Med. 2005;352:1529–38.

    Article  PubMed  CAS  Google Scholar 

  317. Bosca I, Pascual AM, Cassanova B, et al. Four new cases of therapy-related acute promyelocytic leukemia after mitoxantrone. Neurology. 2008;71:457–8.

    Article  PubMed  CAS  Google Scholar 

  318. Hasan SK, Mays AN, Ottone T, et al. Molecular analysis of t(15;17) genomic breakpoints in secondary acute promyelocytic leukemia arising after treatment of multiple sclerosis. Blood. 2008;112:3383–90.

    Article  PubMed  CAS  Google Scholar 

  319. Ramkumar B, Chadra MK, Barcos M, et al. Acute promyelocytic leukemia after mitoxantrone therapy for multiple sclerosis. Cancer Genet Cytogenet. 2008;182:126–9.

    Article  PubMed  CAS  Google Scholar 

  320. Matsuo K, Kiura K, Tahata M, et al. Clustered incidence of acute promyelocytic leukemia during gefitinib treatment of non-small cell lung cancer: experience at a single institution. Am J Hematol. 2006;81:349–54.

    Article  PubMed  CAS  Google Scholar 

  321. Daly PA, Schiffer CA, Wiernik PH. Acute promyelocytic leukemia—Clinical management of 15 patients. Am J Hematol. 1980;8:347.

    Article  PubMed  CAS  Google Scholar 

  322. Biondi A, Luciano A, Bassan R, et al. CD2 expression in acute promyelocytic leukemia is associated with microgranular morphology (FAB M3v) but not with any PML gene breakpoint. Leukemia. 1995;9:1461.

    PubMed  CAS  Google Scholar 

  323. Hazani A, Weidenfeld Y, Tatarsky I, Bental E. Acute promyelocytic leukemia presenting as sudden blindness and sinus vein thrombosis. Am J Hematol. 1988;28:56.

    Article  PubMed  CAS  Google Scholar 

  324. Jetha N. Promyelocytic leukemia with multiorgan infarctions and large vessel thrombosis. Arch Pathol Lab Med. 1981;105:683.

    PubMed  CAS  Google Scholar 

  325. Hoyle CF, Swirsky DM, Freedman L, Hayhoe FGJ. Beneficial effect of heparin in the management of patients with APL. Br J Haematol. 1988;68:283.

    Article  PubMed  CAS  Google Scholar 

  326. Avvisati G, LoCoco F, Mandelli F. Acute promyelocytic leukemia: clinical and morphologic features and prognostic factors. Semin Hematol. 2001;38:4–12.

    Article  PubMed  CAS  Google Scholar 

  327. Lavau C, Dejean A. The t(15;17) translocation in acute promyelocytic leukemia. Leukemia. 1994;8 Suppl 2:S9.

    Google Scholar 

  328. Sessarego M, Fugazza G, Balleari E, et al. High frequency of trisomy 8 in acute promyelocytic leukemia: a fluorescence in situ hybridization study. Cancer Genet Cytogenet. 1997;97:161.

    Article  PubMed  CAS  Google Scholar 

  329. De Botton S, Chevret S, Sanz M, et al. Additional chromosomal abnormalities in patients with acute promyelocytic leukaemia (APL) do not confer poor prognosis: Results of APL 93 trial. Br J Haematol. 2000;111:801.

    Article  PubMed  Google Scholar 

  330. Hernandez JM, Martin G, Gutierrez NC, et al. Additional cytogenetic changes do not influence the outcome of patients with newly diagnosed acute promyelocytic leukemia treated with ATRA plus anthracyclin based protocol. A report of the Spanish group PETHEMA. Haematologica. 2001;86:807.

    PubMed  CAS  Google Scholar 

  331. Schoch C, Haase D, Haferlach T, et al. Incidence and implication of additional chromosome aberrations in acute promyelocytic leukaemia with translocation t(15;17)(q22;q21): A report on 50 patients. Br J Haematol. 1996;94:493.

    Article  PubMed  CAS  Google Scholar 

  332. Slack JL, Arthur DC, Lawrence D, et al. Secondary cytogenetic changes in acute promyelocytic leukemia—prognostic importance in patients treated with chemotherapy alone and association with the intron 3 breakpoint of the PML gene: A Cancer and Leukemia Group B study. J Clin Oncol. 1997;15:1786.

    PubMed  CAS  Google Scholar 

  333. Pantic M, Novak A, Marislavljevic D, et al. Additional chromosome aberrations in acute promyelocytic leukemia: Characteristics and prognostic influence. Med Oncol. 2000;17:307.

    Article  PubMed  CAS  Google Scholar 

  334. Xu L, Zhao WL, Xiong SM, et al. Molecular cytogenetic characterization and clinical relevance of additional complex and/or variant chromosome abnormalities in acute promyelocytic leukemia. Leukemia. 2001;15:1359–68.

    Article  PubMed  CAS  Google Scholar 

  335. Cervera J, Montesinos P, Hernández-Rivas JM, et al. Additional chromosome abnormalities in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Haematologica. 2010;95:424–31.

    Article  PubMed  CAS  Google Scholar 

  336. Batzios C, Hayes LA, He SZ, et al. Secondary clonal cytogenetic abnormalities following successful treatment of acute promyelocytic leukemia. Am J Hematol. 2010;133:484–90.

    Google Scholar 

  337. Dimov ND, Medeiros LJ, Ravandi F, Bueso Ramos CE. Acute promyelocytic leukemia at time of relapse commonly demonstrates cytogenetic evidence of clonal evolution and variability in blast immunophenotypic features. Am J Clin Pathol. 2010;133:454–90.

    Article  Google Scholar 

  338. Grimwade D, Biondi A, Mozziconacci MJ, et al. Characterization of acute promyelocytic leukemia cases lacking the classic 9 t(15:17): Results of the European Working Party. Group Francais de Cytogenetique, 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.

    PubMed  CAS  Google Scholar 

  339. Jansen JH, de Ridder MC, Geertsma WM, et al. Complete remission of t(11;17) positive acute promyelocytic leukemia induced by all-trans retinoic acid and granulocyte colony-stimulating factor. Blood. 1999;94:39.

    PubMed  CAS  Google Scholar 

  340. Krause JR, Stolc V, Kaplan SS, Penchansky L. Microgranular promyelocytic leukemia: a multiparameter examination. Am J Hematol. 1989;30:158.

    Article  PubMed  CAS  Google Scholar 

  341. Murray CK, Estey E, Paietta E, et al. CD56 expression in acute promyelocytic leukemia: a possible indicator of poor treatment outcome? J Clin Oncol. 1999;17:293.

    PubMed  CAS  Google Scholar 

  342. Castoldi GL, Liso V, Specchia G, Tomasi P. Acute promyelocytic leukemia: morphological aspects. Leukemia. 1994;8 Suppl 2:S27.

    PubMed  Google Scholar 

  343. Bennett JM, Catovsky D, Daniel MT, et al. A variant form of hypergranular promyelocytic leukemia (M3). French-American-British (FAB) Co-operative Group. Br J Haematol. 1980;44:169.

    Article  PubMed  CAS  Google Scholar 

  344. Rovelli A, Biondi A, Cantù Rajnoldi A, et al. Microgranular variant of acute promyelocytic leukemia in children. J Clin Oncol. 1992;10:1413.

    PubMed  CAS  Google Scholar 

  345. Davey FR, Davis RB, MacCallum JM, et al. Morphologic and cytochemical characteristics of acute promyelocytic leukemia. Am J Hematol. 1989;30:221.

    Article  PubMed  CAS  Google Scholar 

  346. Tallman MS, Kim HT, Montesinos P, et al. Does microgranular variant morphology of acute promyelocytic leukemia independently predict for a less favorable outcome compared with classical M3 APL? A joint study of the North American Intergroup and the PETHEMA Group. Blood. 2010;116(25):5650–9.

    Article  PubMed  CAS  Google Scholar 

  347. Golomb HM, Rowley JD, Vardiman JW, et al. “Microgranular” acute promyelocytic leukemia: a distinct clinical, ultrastructural, and cytogenetic entity. Blood. 1980;55:253.

    PubMed  CAS  Google Scholar 

  348. McKenna RW, Parkin J, Bloomfield CD, et al. Acute promyelocytic leukemia: a study of 39 cases with identification of a hyperbasophilic microgranular variant. Br J Haematol. 1982;50:201.

    Article  PubMed  CAS  Google Scholar 

  349. Invernizzi R, Iannone AM, Bernuzzi S, et al. Acute promyelocytic leukemia: morphological and clinical features. Haematologica. 1993;78:156.

    PubMed  CAS  Google Scholar 

  350. Tallman MS, Hakimian D, Snower D, et al. Basophilic differentiation in acute promyelocytic leukemia. Leukemia. 1993;7:521.

    PubMed  CAS  Google Scholar 

  351. Erber WN, Asbahr H, Rule SA, Scott CS. Unique immunophenotype of acute promyelocytic leukemia as defined by CD9 and CD68 antibodies. Br J Haematol. 1994;88:101.

    Article  PubMed  CAS  Google Scholar 

  352. Koike T, Tatewaki W, Aoki A, et al. Brief report: severe symptoms of hyperhistaminemia after the treatment of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med. 1992;327:385.

    Article  PubMed  CAS  Google Scholar 

  353. Gilbert RD, Karabus CD, Mills E. Acute promyelocytic leukemia: a childhood cluster. Cancer. 1987;59:933.

    Article  PubMed  CAS  Google Scholar 

  354. Williams CKO, Folani AO, Saditan AAO, et al. Childhood acute leukemia in a tropical population. Br J Cancer. 1982;42:89.

    Article  Google Scholar 

  355. Scott RM, Mayer RJ. The unique aspects of acute promyelocytic leukemia. J Clin Oncol. 1990;8:1913.

    Google Scholar 

  356. Masamoto Y, Nannya Y, Arai S, et al. Evidence for basophilic differentiation of acute promyelocytic leukemia cells during arsenic trioxide therapy. Br J Hematol. 2009;144:798–9.

    Article  Google Scholar 

  357. Das Gupta A, Sapre RS, Shah AS, et al. Cytochemical and immunophenotypic heterogeneity in acute promyelocytic leukemia. Acta Haematol. 1989;81:5.

    Article  PubMed  CAS  Google Scholar 

  358. Scott CS, Patel D, Drexler HG, et al. Immunophenotypic and enzymatic studies do not support the concept of mixed monocytic-granulocytic differentiation in acute promyelocytic leukemia (M3): A study of 44 cases. Br J Haematol. 1989;71:50.

    Article  Google Scholar 

  359. Drexler HG. Classification of acute myeloid leukemia: a comparison of FAB and immunophenotyping. Leukemia. 1987;1:697.

    PubMed  CAS  Google Scholar 

  360. Sanz MA, Jarque I, Martín G, et al. Acute promyelocytic leukemia. Therapy results and prognostic factors. Cancer. 1988;61:7.

    Article  PubMed  CAS  Google Scholar 

  361. Breccia M, Carmosino I, Diverio D, et al. Early detection of meningeal localization in acute promyelocytic leukemia patients with high presenting leucocyte count. Br J Haematol. 2003;120:266–70.

    Article  PubMed  Google Scholar 

  362. Nagai S, Nammya Y, Arai S, et al. Molecular and cytogenetic monitoring and preemptive therapy for central nervous system relapse of acute promyelocytic leukemia. Haematologica. 2010;95:169–71.

    Article  PubMed  CAS  Google Scholar 

  363. Kaspers G, Gibson B, Grimwade D, et al. Central nervous system involvement in relapsed acute promyelocytic leukemia. Pediatr Blood Cancer. 2009;53:235–6.

    Article  PubMed  Google Scholar 

  364. Montesinos P, Díaz-Mediavilla J, Debén G, et al. Central nervous involvement at first relapse in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline monotherapy without intrathecal prophyllaxis. Haematologica. 2009;94:1242–9.

    Article  PubMed  CAS  Google Scholar 

  365. Akoz AG, Dagdas S, Oget G, et al. Isolated central nervous system relapse during cytologic and molecular hematologic remission in two patients with acute promyelocytic leukemia. Hematology. 2007;12:419–22.

    Article  PubMed  Google Scholar 

  366. Vega-Ruíz A, Faderl S, Estrov Z, et al. Incidence of extrameullary disease in patients with acute promyelocytic leukemia: a single-institution experience. Int J Hematol. 2009;89:489–96.

    Article  PubMed  Google Scholar 

  367. Ko B-S, Tang J-L, Chen Y-C, et al. Extramedullary relapse after all-trans retinoic acid treatment in acute promyelocytic leukemia—the occurrence of retinoic acid syndrome is a risk factor. Leukemia. 1999;13:1406.

    Article  PubMed  CAS  Google Scholar 

  368. de Botton S, Sanz MA, Chevret S, et al. Extramedullary relapse in acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Leukemia. 2006;20:35–41.

    Article  PubMed  CAS  Google Scholar 

  369. De Renzo A, Santoro LFE, Notaro R, et al. Acute promyelocytic leukemia after treatment for non-Hodgkin’s lymphoma with drugs targeting topoisomerase II. Am J Hematol. 1999;60:300.

    Article  PubMed  Google Scholar 

  370. Kantarjian HM, Keating MJ, Walters RS, et al. The association of specific “favorable” cytogenetic abnormalities with secondary leukemia. Cancer. 1986;58:924.

    Article  PubMed  CAS  Google Scholar 

  371. Detourmignies L, Castaigne S, Stoppa AM, et al. Therapy-related acute promyelocytic leukemia: A report of 16 cases. J Clin Oncol. 1992;10:1430.

    PubMed  CAS  Google Scholar 

  372. Hall MJ, Li L, Wiernik PH, Olopade OI. BRCA2 mutation and the risk of hematologic malignancy. Leuk Lymphoma. 2006;47:765–7.

    PubMed  Google Scholar 

  373. Castaigne S, Berger R, Jolly V, et al. Promyelocytic blast crisis of chronic myelocytic leukemia with both t(9;22) and t(15;17) in M3 cells. Cancer. 1984;54:2409.

    Article  PubMed  CAS  Google Scholar 

  374. Rosenthal NS, Knapp D, Farhi DC. Promyelocytic blast crisis of chronic myelogenous leukemia. A rare subtype associated with disseminated intravascular coagulation. Am J Clin Pathol. 1995;103:185.

    PubMed  CAS  Google Scholar 

  375. Misawa S, Lee E, Schiffer CA, et al. Association of the translocation (15;17) with malignant proliferation of promyelocytes in acute leukemia and chronic myelogenous leukemia at blast crisis. Blood. 1986;67:270.

    PubMed  CAS  Google Scholar 

  376. Hogge DE, Misawa S, Schiffer CA, Testa JR. Promyelocytic blast crisis in chronic granulocytic leukemia with 15;17 translocation. Leuk Res. 1984;6:1019.

    Article  Google Scholar 

  377. Wiernik PH, Dutcher JP, Paietta E, et al. Treatment of promyelocytic blast crisis of chronic myelogenous leukemia with all transretinoic acid. Leukemia. 1991;5:504.

    PubMed  CAS  Google Scholar 

  378. Hatzis T, Standen GR, Howell RT, et al. Acute promyelocytic leukaemia (M3): Relapse with acute myeloblastic leukaemia (M2) and dic(5;17)(q11;p11). Am J Hematol. 1995;48:40.

    Article  PubMed  CAS  Google Scholar 

  379. Bseiso AN, Kantarjian H, Estey E. Myelodysplastic syndrome following successful therapy of acute promyelocytic leukemia. Leukemia. 1977;11:168.

    Article  Google Scholar 

  380. Felice MS, Rossi J, Gallego M, et al. Acute trilineage leukemia with monosomy of chromosome 7 following an acute promyelocytic leukemia. Leuk Lymphoma. 1999;34:409.

    PubMed  CAS  Google Scholar 

  381. Zompi S, Legrand O, Bouscany D, et al. Therapy-related acute myeloid leukemia after successful therapy for acute promyelocytic leukaemia with t(15;17): A report of two cases and a review of the literature. Br J Haematol. 2000;110:610.

    Article  PubMed  CAS  Google Scholar 

  382. Park TS, Choi JR, Yoon SH, et al. Acute promyelocytic leukemia relapsing as secondary acute myelogenous leukemia with translocation t(3;21)(q26;q22) and RUNX1-MDS1-EV11 fision transcript. Cancer Genet Cytogenet. 2008;187:61–73.

    Article  PubMed  CAS  Google Scholar 

  383. Di Bona E, Avvisati G, Castaman G, et al. Early haemorrhagic morbidity and mortality during remission induction with or without all-trans retinoic acid in acute promyelocytic leukaemia. Br J Haematol. 2000;108:689.

    Article  PubMed  Google Scholar 

  384. Visani G, Gugliotta L, Tosi P, et al. All-trans retinoic acid significantly reduces the incidence of early hemorrhagic death during induction therapy of acute promyelocytic leukemia. Eur J Haematol. 2000;64:139.

    Article  PubMed  CAS  Google Scholar 

  385. Yates JW, Wallace Jr J, Ellison RR, Holland JF. Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer Chemother Rep. 1973;57:485.

    PubMed  CAS  Google Scholar 

  386. Estey E, Thall PF, Pierce S, et al. Treatment of newly diagnosed acute promyelocytic leukemia without cytarabine. J Clin Oncol. 1997;15:483.

    PubMed  CAS  Google Scholar 

  387. Sanz MA, Guillermo M, Rayon C, et al. A modified AIDA protocol with anthracycline-based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/RARα-positive acute promyelocytic leukemia. Blood. 1999;94:3015.

    PubMed  CAS  Google Scholar 

  388. Head DR, Kopecky KJ, Weick J, et al. Effect of aggressive daunomycin therapy on survival in acute promyelocytic leukemia. Blood. 1995;86:1717.

    PubMed  CAS  Google Scholar 

  389. Pallavicini EB, Luliri P, Anselmetti L, et al. High-dose daunorubicin (DNR) for induction and treatment of relapse in acute promyelocytic leukemia (APL): Report of 17 cases. Haematologica. 1988;73:49.

    Google Scholar 

  390. Carotenuto M, Greco M, Bavaro P et al. Acute promyelocytic leukemia: Results of treatment of 10 cases (Abstr). In: Proceedings of the 3 rd International Symposium on Therapy of Acute Leukemias, 1982.

    Google Scholar 

  391. Salvaneschi L, Lazzarino M, Morra E et al. Survival in adult acute myeloid leukemia under conventional chemotherapy (Abstr). In: Proceedings of the 3 rd International Symposium on Therapy of Acute Leukemias, 1982.

    Google Scholar 

  392. Marty M, Ganem G, Fisher J, et al. Leucémie aiguë promyélocytaire. Étude rétrospective de 119 malades traités par daunorubicine. Novu Rev Fr Hématol. 1984;26:371.

    CAS  Google Scholar 

  393. Mandelli F, Petti MC, Avvisati G, et al. GIMEMA experience in the treatment of adult myelogenous. In: Gale RP, editor. Acute myelogenous leukemia: progress and controversies. New York: Wiley-Liss; 1990. p. 273.

    Google Scholar 

  394. Petti MC, Avvisati G, Amadori S, et al. Acute promyelocytic leukemia: clinical aspects and results of treatment in 62 patients. Haematologica. 1987;72:151.

    PubMed  CAS  Google Scholar 

  395. Bennett JM, Andersen JW, Cassileth PA. Long term survival in acute myeloid leukemia: The Eastern Cooperative Oncology Group. Leuk Res. 1991;15:223.

    Article  PubMed  CAS  Google Scholar 

  396. Clarkson B. Retinoic acid in acute promyelocytic leukemia: the promise and the paradox. Cancer Cells. 1991;3:211.

    PubMed  CAS  Google Scholar 

  397. Fenaux P, Pollet JP, Vandenbossche-Simon L, et al. Treatment of acute promyelocytic leukemia: a report of 70 cases. Leuk Lymphoma. 1991;4:239.

    Article  Google Scholar 

  398. Head DR, Kopecky K, Hewlett J, et al. Survival with cytotoxic therapy in acute promyelocytic leukemia, a SWOG report. Blood. 1991;78:268a.

    Google Scholar 

  399. Thomas X, Archimbaud E, Treille-Ritouet D, et al. Prognostic factors in acute promyelocytic leukemia: a retrospective study of 67 cases. Leuk Lymphoma. 1991;4:249.

    Article  Google Scholar 

  400. Willemze R, Suciu S, Mandelli F, et al. Treatment of patients with acute promyelocytic leukemia. The EORTC-LCG experience. Leukemia. 1994;8 Suppl 2:S48.

    PubMed  Google Scholar 

  401. Adẻs L, Chevret S, Raffoux E, et al. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European acute promyelocytic leukemia group. J Clin Oncol. 2006;24:5703–54710.

    Article  PubMed  CAS  Google Scholar 

  402. Sanz MA, Montesinos P, Rayón C, 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. 2010;115:5137–46.

    Article  PubMed  CAS  Google Scholar 

  403. Imaizumi M, Tawa A, Hanada R, et al. Prospective study of a therapeutic regimen with all-trans retinoic acid and anthracyclines in combination of cytarabine in children with acute promyeocytic leukaemia: the Japanese childhood acute myeloid leukaemia cooperative study. Br J Haematol. 2011;152(1):89–98.

    Article  PubMed  CAS  Google Scholar 

  404. Lengfelder E, Reichert A, Schoch C, et al. Double induction strategy including high dose cytarabine in combination with all-trans retinoic acid: effects in patients with newly diagnosed acute promyelocytic leukemia. Leukemia. 2000;14:1362.

    Article  PubMed  CAS  Google Scholar 

  405. Berman E. A review of idarubicin in acute leukemia. Oncology. 1993;7:91.

    PubMed  CAS  Google Scholar 

  406. Berman E, Heller G, Santorsa J, et al. Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. Blood. 1991;77:1666.

    PubMed  CAS  Google Scholar 

  407. Wiernik PH, Banks PLC, Case Jr DC, et al. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood. 1992;79:313.

    PubMed  CAS  Google Scholar 

  408. Avvisati G, Mandelli F, Petti MC, et al. Idarubicin (4-demethoxy-daunorubicin) as a single agent for remission induction of previously untreated acute promyelocytic leukemia: a pilot study of the Italian cooperative group GIMEMA. Eur J Haematol. 1990;44:257.

    Article  PubMed  CAS  Google Scholar 

  409. Avvisati G, LoCoco F, Diverio D, 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;88:1390–8.

    PubMed  CAS  Google Scholar 

  410. Mandelli F, Diverio D, Avvisati G, et al. Molecular remission in PML/RARα-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dell’Adulto and Associazione Italiana de Ematologia ed Oncologia Pediatria Cooperative Groups. Blood. 1997;90:1014–21.

    PubMed  CAS  Google Scholar 

  411. Sanz MA, Martín G, Rayón C, et al. A modified AIDA protocol with anthracycline-based consolidation results in high antileukemia efficacy and reduced toxicity in newly diagnosed PML/RARα-positive acute promyelocytic leukemia. PETHEMA group. Blood. 1999;94:3015–21.

    PubMed  CAS  Google Scholar 

  412. Sanz MA, LoCoco F, Martín G, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA Cooperative Groups. Blood. 2000;96:1247–53.

    PubMed  CAS  Google Scholar 

  413. Sanz MA, Martín G, González M, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid an anthracycline monotherapy: a multicenter study by the PETHEMA group. Blood. 2004;103:1237–43.

    Article  PubMed  CAS  Google Scholar 

  414. Lengfelder E, Haferlach C, Saussele S, et al. High dose ara-C in the treatment of newly diagnosed acute promyelocytic leukemia: long-term results of the German AMLCG. Leukemia. 2009;23:2248–58.

    Article  PubMed  CAS  Google Scholar 

  415. Tallman MS, Rowe JM. Acute promyelocytic leukemia: a paradigm for differentiation therapy with retinoic acid. Blood Rev. 1994;8:70.

    Article  PubMed  CAS  Google Scholar 

  416. Haferlach T, Löffler H, Glass B, Gassmann W. Repeated complete remission in a patient with acute promyelocytic leukemia after treatment with 13-cis-retinoic acid first and with all-trans-retinoic acid in relapse. Clin Invest. 1993;71:774.

    Article  CAS  Google Scholar 

  417. Muindi J, Frankel S, Huselton C, et al. Clinical pharmacology of oral all-trans retinoic acid with acute promyelocytic leukemia. Cancer Res. 1992;52:2138.

    PubMed  CAS  Google Scholar 

  418. Lefebvre P, Thomas G, Gourmel B, et al. Pharmacokinetics of oral all-trans retinoic acid with acute promyelocytic leukemia. Leukemia. 1991;5:1054.

    PubMed  CAS  Google Scholar 

  419. Muindi J, Frankel S, Miller Jr WH, 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. 1992;79:299.

    PubMed  CAS  Google Scholar 

  420. Smith MA, Adamson PC, Balis FM, et al. Phase I trial and pharmacokinetic evaluation of all-trans-retinoic acid in pediatric patients. J Clin Oncol. 1992;10:1666.

    PubMed  CAS  Google Scholar 

  421. Meyskens Jr FL, Goodman GE, Alberts DS. 13-cis-retinoic acid: pharmacology, toxicology and clinical applications for the prevention and treatment of human cancer. Crit Rev Oncol Hematol. 1985;13:75.

    Article  Google Scholar 

  422. Brazzell RK, Vane FM, Ehmann CW, et al. Pharmacokinetics of isotretinoin during repetitive dosing to patients. Eur J Clin Pharmacol. 1983;24:69.

    Article  Google Scholar 

  423. Adamson PC, Balis FM, Smith MA, et al. Dose-dependent pharmacokinetics of all-trans-retinoic acid. J Natl Cancer Inst. 1992;84:1332.

    Article  PubMed  CAS  Google Scholar 

  424. Schwartz EL, Hallam S, Gallagher RE, Wiernik PH. Inhibition of all-trans retinoic acid metabolism by fluconazole in vitro and in patients with acute promyelocytic leukemia. Mol Pharmacol. 1995;50:923.

    CAS  Google Scholar 

  425. Miller VA, Rigas JR, Muindi JRF, et al. Modulation of all-trans retinoic acid pharmacokinetics by liarozole. Cancer Chemother Pharmacol. 1994;34:522.

    Article  PubMed  CAS  Google Scholar 

  426. Muindi JF, Scher HI, Rigas JR, et al. Elevated plasma lipid peroxide content correlates with rapid plasma clearance of all-trans-retinoic acid in patients with advanced cancer. Cancer Res. 1994;54:2125.

    PubMed  CAS  Google Scholar 

  427. Agadir A, Cornic M, Lefebvre P, et al. All-trans retinoic acid pharmacokinetics and bioavailability in acute promyelocytic leukemia: Intracellular concentrations and biologic response relationship. J Clin Oncol. 1995;13:2517.

    PubMed  CAS  Google Scholar 

  428. Degos L, Chomienne C, Daniel MT, et al. All-trans-retinoic acid treatment for patients with acute promyelocytic leukemia. In: Saurat J-H, editor. Retinoids: 10 years on. Basel: Karger; 1991. p. 121.

    Google Scholar 

  429. Chen Z-X, Xue Y-Q, Zhang R, et al. A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukemia patients. Blood. 1991;78:1413.

    PubMed  CAS  Google Scholar 

  430. Vahdat L, Maslak P, Miller Jr W, et al. Early mortality and the retinoic acid syndrome in acute promyelocytic leukemia: Impact of leukocytosis, low-dose chemotherapy, PML/RAR-α isoform, and CD13 expression in patients treated with all-trans retinoic acid. Blood. 1994;84:3843.

    PubMed  CAS  Google Scholar 

  431. Fenaux P, Degos L. Treatment of acute promyelocytic leukemia with all trans retinoic acid. Leuk Res. 1991;8:655.

    Article  Google Scholar 

  432. Fenaux P, Castaigne S, Dombret H, et al. All-trans retinoic acid followed by intensive chemotherapy gives a high complete remission rate and may prolong remissions in newly diagnosed acute promyelocytic leukemia: A pilot study on 26 cases. Blood. 1992;80:2176.

    PubMed  CAS  Google Scholar 

  433. Fenaux P, Le Deley MC, Castaigne S, et al. Effect of all trans retinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. Blood. 1993;82:3241.

    PubMed  CAS  Google Scholar 

  434. Fenaux P, Chevret S, Guerci A, et al. Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia. Leukemia. 2000;14:1371.

    Article  PubMed  CAS  Google Scholar 

  435. Kawai Y, Watanabe K, Kizaki M, et al. Rapid improvement of coagulopathy by all-trans retinoic acid in acute promyelocytic leukemia. Am J Hematol. 1994;46:184.

    Article  PubMed  CAS  Google Scholar 

  436. Kanamaru A, Takemoto Y, Tanimoto M, et al. All-trans retinoic acid for the treatment of newly diagnosed acute promyelocytic leukemia. Blood. 1995;85:1202.

    PubMed  CAS  Google Scholar 

  437. Burnett AK, Grimwade D, Solomon E, et al. 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.

    PubMed  CAS  Google Scholar 

  438. Estey E, Koller C, Cortes J, et al. Treatment of newly-diagnosed acute promyelocytic leukemia with liposomal all-trans retinoic acid. Leuk Lymphoma. 2001;42:309.

    Article  PubMed  CAS  Google Scholar 

  439. Douer D, Estey E, Santillana S, et al. Treatment of newly diagnosed and relapsed acute promyelocytic leukemia with intravenous liposomal all-trans retinoic acid. Blood. 2001;97:73.

    Article  PubMed  CAS  Google Scholar 

  440. Warrell Jr RP, Maslak P, Eardley A, et al. Treatment of acute promyelocytic leukemia with all-trans retinoic acid: an update of the New York experience. Leukemia. 1994;8 Suppl 2:S33.

    PubMed  Google Scholar 

  441. de Botton S, Chevret S, Coiteux V, et al. Early onset of chemotherapy can reduce the incidence of ATRA syndrome in newly diagnosed acute promyelocytic leukemia (APL) with low white blood cell counts: results from APL 93 trial. Leukemia. 2003;17:339–42.

    Article  PubMed  CAS  Google Scholar 

  442. Visani G, Tosi P, Cenacchi A, et al. Pre-treatment with all-trans retinoic acid accelerates polymorphonuclear recovery after chemotherapy in patients with acute promyelocytic leukemia. Leuk Lymphoma. 1994;15:143.

    Article  PubMed  CAS  Google Scholar 

  443. de la Serna J, Montesinos P, Vellenga E, et al. Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin. Blood. 2008;111:3395–402.

    Article  PubMed  CAS  Google Scholar 

  444. Castaigne S, Lefebvre P, Chomienne C, et al. Effectiveness and pharmacokinetics of low-dose all-trans retinoic acid (25 mg/m2) in acute promyelocytic leukemia. Blood. 1993;82:3560.

    PubMed  CAS  Google Scholar 

  445. Fenaux P, Chastang C, Chomienne C, et al. Treatment of newly diagnosed acute promyelocytic leukemia (APL) by all transretinoic acid (ATRA) combined with chemotherapy: The European experience. Leuk Lymphoma. 1995;16:431.

    Article  PubMed  CAS  Google Scholar 

  446. Fenaux P, Chastange C, Chevret S, 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;94:1192–200.

    PubMed  CAS  Google Scholar 

  447. Adẻs L, Guerci A, Raffoux E, et al. Very long-term outcome of acute promyelocytic after treatment with all-trans retinoic acid and chemotherapy: the European APL long experience. Blood. 2010;115:1690–6.

    Article  PubMed  CAS  Google Scholar 

  448. Levin A, Sturzenbecker L, Kazmer S, et al. 9-cis retinoic acid stereoisomer binds and activates the nuclear receptor RXRα. Nature. 1992;355:359.

    Article  PubMed  CAS  Google Scholar 

  449. Tobita T, Takeshita A, Kitamura K, et al. Treatment with a new synthetic retinoid, AN80, of acute promyelocytic leukemia relapsed from complete remission induced by all-trans retinoic acid. Blood. 1997;90:967–73.

    PubMed  CAS  Google Scholar 

  450. Shinjo K, Takeshita A, Ohnishi K, et al. Good prognosis of patients with acute promyelocytic leukemia who achieved second complete remission (CR) with a new retinoid, AM80, after relapse from CR induced by all-trans-retinoic acid. Int J Hematol. 2000;72:470–3.

    PubMed  CAS  Google Scholar 

  451. Di Veroli A, Ramadan SM, Divona M, et al. Molecular remission in advanced acute promyelocytic leukaemia after treatment with the oral synthetic retinoid Tamibarotene. Br J Haematol. 2010;151(1):99–101.

    Article  PubMed  Google Scholar 

  452. Visani G, Zauli G, Ottaviani E, et al. All-trans retinoic acid potentiates megakaryocyte colony formation: In vitro and in vivo effects after administration to acute promyelocytic leukemia patients. Leukemia. 1994;8:2183.

    PubMed  CAS  Google Scholar 

  453. Visani G, Ottaviani E, Zauli G, et al. All-trans retinoic acid at low concentration directly stimulates normal adult megakaryocytopoiesis in the presence of thrombopoietin or combined cytokines. Eur J Haematol. 1999;63:149.

    Article  PubMed  CAS  Google Scholar 

  454. Kini AR, Peterson LA, Tallman MS, Lingen MW. Angiogenesis in acute promyelocytic leukemia: induction by vascular endothelial growth factor and inhibition by all-trans retinoic acid. Blood. 2001;97:3919.

    Article  PubMed  CAS  Google Scholar 

  455. Gianni M, Kalac Y, Ponzanelli I, et al. Tyrosine kinase inhibitor STI571 potentiates the pharmacologic activity of retinoic acid in acute promyelocytic leukemia cells: Effects on the degradation of RARα and PML-RARα. Blood. 2001;97:3234.

    Article  PubMed  CAS  Google Scholar 

  456. Sassano A, Katsoilidis E, Antico G, et al. Suppressive effects of statins on acute promyelocytic leukemia cells. Cancer Res. 2007;67:4524–32.

    Article  PubMed  CAS  Google Scholar 

  457. Tomiyama N, Matzno S, Kitada C, et al. The possibility of simvastatin as a chemotherapeutic agent for all-trans retinoic acid-resistant promyelocytic leukemia. Biol Pharm Bull. 2008;31:369–74.

    Article  PubMed  CAS  Google Scholar 

  458. Frankel SR, Eardley A, Lauwers G, et al. The “retinoic acid syndrome” in acute promyelocytic leukemia. Ann Intern Med. 1992;117:292.

    PubMed  CAS  Google Scholar 

  459. Tallman MS, Andersen JW, Schiffer CA, et al. Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome. Blood. 2000;95:90–5.

    PubMed  CAS  Google Scholar 

  460. Montesinos P, Bergua M, Vellenga E, et al. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood. 2009;113:775–83.

    Article  PubMed  CAS  Google Scholar 

  461. Jeddi R, Ghédira H, Amor RB, et al. Recurrent differentiation syndrome or septic shock? Unresolved dilemma in a patient with acute promyelocytic leukemia. Med Oncol. 2011;28(1):279–81.

    Article  PubMed  Google Scholar 

  462. Wiley JS, Firkin FC. Reduction of pulmonary toxicity by prednisolone prophylaxis during all-trans retinoic acid treatment of acute promyelocytic leukemia. Australian Leukemia Study Group. Leukemia. 1995;9:774–8.

    PubMed  CAS  Google Scholar 

  463. Raanani P, Segal E, Levi I, et al. Diffuse alveolar hemorrhage in acute promyelocytic leukemia patients treated with ATRA- a manifestation of the basic disease or the treatment. Leuk Lymphoma. 2000;37:605–10.

    Article  PubMed  CAS  Google Scholar 

  464. Saiki I, Fujii H, Yeneda J, et al. Role of aminopeptidase N (CD13) in tumor cell invasion and extracellular matrix degeneration. Intl J Cancer. 1993;54:137.

    Article  CAS  Google Scholar 

  465. Cunha de Santis G, Tamarozzi MB, Sousa RB, et al. Adhesion molecules and differentiation syndrome: phenotypic and functional analysis of the effect of ATRA, As2O3, phenylbutyrate, and G-CSF in acute promyelocytic leukemia. Haematologica. 2007;92:1615–22.

    Article  PubMed  CAS  Google Scholar 

  466. Luesink M, Pennings JL, Wissink WM, et al. Chemokine induction by all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia: triggering the differentiation syndrome. Blood. 2009;114:5512–21.

    Article  PubMed  CAS  Google Scholar 

  467. Luesink M, Jansen JH. Advances in understanding the pulmonary infiltration in acute promyelocytic leukaemia. Br J Haematol. 2010;151(3):209–20.

    Article  PubMed  CAS  Google Scholar 

  468. Csomós K, Nẻmet I, Fésűs L, Balajithy Z. Tissue transglutaminase contributes to the all-trans retinoic acid induced differentiation syndrome phenotype in the NB4 model of acute promyelocytic leukemia. Blood. 2010;116(19):3933–43.

    Article  PubMed  CAS  Google Scholar 

  469. Hakimian D, Tallman MS, Zugerman C, et al. Erythema nodosum associated with all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Leukemia. 1993;7:758.

    PubMed  CAS  Google Scholar 

  470. Gallipoli P, Drummond MW. Pseudotumour cerebri as a manageable side effect of prolonged all-trans retinoic acid therapy in an adult patient with acute promyelocytic leukaemia. Eur J Haematol. 2009;82:242–3.

    Article  PubMed  Google Scholar 

  471. Kesler A, Kliper E, Assayag EB, et al. Thrombophilic factors in idiopathic intracranial hypertension: a report of 51 patients and a meta-analysis. Blood Coagul Fibrinolysis. 2010;21:328–33.

    Article  PubMed  CAS  Google Scholar 

  472. Shirono K, Kiyofuji C, Tsuda H. Sweet’s syndrome in a patient with acute promyelocytic leukemia during treatment with alltrans retinoic acid. Int J Hematol. 1995;62:183.

    Article  PubMed  CAS  Google Scholar 

  473. Christ E, Linka A, Jacky E, et al. Sweet’s syndrome involving the musculoskeletal system during treatment of promyelocytic leukemia with all-trans retinoic acid. Leukemia. 1996;10:731.

    PubMed  CAS  Google Scholar 

  474. Torromeo C, Latagliata R, Avvisati G, et al. Intraventricular thrombosis during all-trans retinoic acid treatment in acute promyelocytic leukemia. Leukemia. 2000;15:1311.

    Article  Google Scholar 

  475. Losada R, Espinosa E, Hernandez C, et al. Thrombocytosis in patients with acute promyelocytic leukaemia during all-trans retinoic acid treatment. Br J Haematol. 1996;95:704.

    Article  PubMed  CAS  Google Scholar 

  476. Kentos A, Le Moine F, Crenier L, et al. All-trans retinoic acid induced thrombocytosis in a patient with acute promyelocytic leukaemia. Br J Haematol. 1997;97:685.

    PubMed  CAS  Google Scholar 

  477. Montesinos P, Gozález JD, Gozález J, et al. Therapy-related myeloid neoplasms in patients with acute promyelocytic leukemia treated with all-trans-retinoic acid and anthracycline-based chemotherapy. J Clin Oncol. 2010;28:3872–9.

    Article  PubMed  CAS  Google Scholar 

  478. Gore SD, Gojo I, Sekeres MA, et al. Single cycle of arsenic trioxide-based consolidation chemotherapy spares anthracycline exposure in the primary management of acute promyelocytic leukemia. J Clin Oncol. 2010;28:1047–53.

    Article  PubMed  CAS  Google Scholar 

  479. Dai CW, Zhang GS, Shen JK, et al. Use of all-trans retinoic acid in combination with arsenic trioxide for remission induction in patients with newly diagnosed acute promyelocytic leukemia and for consolidation/maintenance in CR patients. Acta Haematol. 2009;121:1–8.

    Article  PubMed  CAS  Google Scholar 

  480. Hu J, Liu YF, Wu CF, 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. 2009;106:3342–7.

    Article  PubMed  CAS  Google Scholar 

  481. Rvandi F, Estey E, Jones D, et al. Effective treatment of acute promyelocytic leukemia with all-trans retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol. 2009;27:504–10.

    Article  CAS  Google Scholar 

  482. Estey E, Garcia-Manero G, Ferrajoli A, et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006;108:3469–73.

    Article  CAS  Google Scholar 

  483. Zhou J, Zhang Y, Li J, et al. Single-agent arsenic trioxide in the treatment of children with newly diagnosed acute promyelocytic leukemia. Blood. 2010;115:1697–702.

    Article  PubMed  CAS  Google Scholar 

  484. Mathews V, George B, Chendamarai E, et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J Clin Oncol. 2010;28:3866–71.

    Article  PubMed  CAS  Google Scholar 

  485. Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup study C9710. Blood. 2010;116(19):3751–7.

    Article  PubMed  CAS  Google Scholar 

  486. Yedjou C, Thuisseu L, Tchounwou C, et al. Ascorbic acid potentiation of arsenic trioxide anticancer activity against acute promyelocytic leukemia. Arch Drug Inf. 2009;2:59–65.

    Article  PubMed  CAS  Google Scholar 

  487. Chang JE, Voorhees PM, Kolesar JM, et al. Phase II study of arsenic trioxide and ascorbic acid for relapsed or refractory lymphoid malignancies: Wisconsin Oncology Network study. Hematol Oncol. 2009;27:11–6.

    Article  PubMed  CAS  Google Scholar 

  488. Kuroki M, Ariumi Y, Ikeda M, et al. Arsenic trioxide inhibits hepatitis C virus RNA replication through modulation of the glutathione redox system and oxidative stress. J Virol. 2009;83:2338–48.

    Article  PubMed  CAS  Google Scholar 

  489. Avvisanti G, Lo Coco F, Diverio D, 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;88:1390–8.

    Google Scholar 

  490. Avvisati G, Petti MC, Lo-Coco F, et al. Induction therapy with idarubicin alone significantly influences event-free survival duration in patients with newly diagnosed hypergranular acute promyelocytic leukemia: final results of the GIMEMA randomized study LAP 0389 with 7 years minimal follow-up. Blood. 2002;100:3141–6.

    Article  PubMed  CAS  Google Scholar 

  491. Sanz MA, Lo Coco F, Martín G. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PTHEMA and HIMEMA cooperative groups. Blood. 2000;96:1247–53.

    PubMed  CAS  Google Scholar 

  492. Lengfelder E, Haerlach C, Saussele S, et al. High dose ara-C in the treatment of newly diagnosed acute promyelocytic leukemia: long-term results of the German AMLCG. Leukemia. 2009;23:2248–58.

    Article  PubMed  CAS  Google Scholar 

  493. Adẻs L, Sanz MA, Chevret S, et al. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008;111:1078–84.

    Article  PubMed  Google Scholar 

  494. Kelaidi C, Chevret S, De Botton S, et al. Improved outcome of acute promyelocytic leukemia with high WBC counts over the last 15 years: the European APL Group experience. J Clin Oncol. 2009;27:2668–76.

    Article  PubMed  Google Scholar 

  495. Dutcher JP, Wiernik PH, Markus S, et al. Intensive maintenance therapy improves survival in adult acute nonlymphocytic leukemia: an eight-year follow-up. Leukemia. 1988;2:413.

    PubMed  CAS  Google Scholar 

  496. Kantarjian HM, Keating MJ, Walters RS, et al. Role of maintenance chemotherapy in acute promyelocytic leukemia. Cancer. 1987;59:1258.

    Article  PubMed  CAS  Google Scholar 

  497. Tallman MS, Andersen JW, Schiffer CA, et al. All-trans retinoic acid in acute promyelocytic leukemia. N Engl J Med. 1997;337:1021.

    Article  PubMed  CAS  Google Scholar 

  498. Tallman MS, Andersen JW, Schiffer CA, et al. All-trans retinoic acid in acute promyelocytic leukemia: Long-term outcome results and prognostic factor analysis from the North American Inter- group protocol. Blood. 2002;100:4298.

    Article  PubMed  CAS  Google Scholar 

  499. Asou N, Kishimoto Y, Kiyoi H, et al. A randomized study with or without intensified maintenance chemotherapy in patients with acute promyelocytic leukemia who have become negative for PML-RARα transcript after consolidation therapy: Japan Adilt Leukemia Study Group (JALSG) APL97 study. Blood. 2007;110:59–66.

    Article  PubMed  CAS  Google Scholar 

  500. Grimwade D, Jovanovic JV, Hills RK, et al. Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy. J Clin Oncol. 2009;27:3650–2358.

    Article  PubMed  CAS  Google Scholar 

  501. Lo Coco F, Diverio D, Avvisati G, et al. Therapy of molecular relapse in acute promyelocytic leukemia. Blood. 1999;94:2225.

    PubMed  CAS  Google Scholar 

  502. Esteve J, Escoda L, Martín G, et al. Outcome of patients with acute promyelocytic leukemia failing to frontline treatment with all-trans retinoic acid and anthracycline-based chemotherapy (PETHEMA protocols LPA96 and LPA99): benefit of an early intervention. Leukemia. 2007;21:446–52.

    Article  PubMed  CAS  Google Scholar 

  503. Cortes JE, Kantarjian H, O’Brien S, et al. All-trans retinoic acid followed by chemotherapy for salvage of refractory or relapsed acute promyelocytic leukemia. Cancer. 1994;73:2946.

    Article  PubMed  CAS  Google Scholar 

  504. Miller Jr WH, Jakubowski A, Tong WP, et al. 9-cis retinoic acid induces complete remission but does not reverse clinically acquired retinoid resistance in acute promyelocytic leukemia. Blood. 1995;85:3021.

    PubMed  CAS  Google Scholar 

  505. Soignet SL, Benedetti F, Fleishauer A, et al. Clinical study of 9-cis retinoic acid (LGD1057) in acute promyelocytic leukemia. Leukemia. 1998;12:15118.

    Article  CAS  Google Scholar 

  506. Takeshita A, Shibata Y, Shinjo K, et al. Successful treatment of relapse of acute promyelocytic leukemia with a new synthetic retinoid, Am80. Ann Intern Med. 1996;124:893.

    PubMed  CAS  Google Scholar 

  507. Warrell Jr RP, He LZ, Richon V, et al. Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Natl Cancer Inst. 1998;90:1621.

    Article  PubMed  CAS  Google Scholar 

  508. Thomas X, Dombret H, Cordonnier C, et al. Treatment of relapsing acute promyelocytic leukemia by all-trans retinoic acid therapy followed by timed sequential chemotherapy and stem cell transplantation. Leukemia. 2000;14:1006.

    Article  PubMed  CAS  Google Scholar 

  509. Jurcic JG, DeBlasio T, Dumont L, et al. Molecular remission induction with retinoic acid and anti-CD33 monoclonal antibody HuM195 in acute promyelocytic leukemia. Clin Cancer Res. 2000;6:372.

    PubMed  CAS  Google Scholar 

  510. Aulde J. A study of the pharmacology and therapeutics of arsenic. NY Med J. 1891;53:390.

    Google Scholar 

  511. Shen ZX, Chen GQ, Ni JH, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997;89:3354.

    PubMed  CAS  Google Scholar 

  512. Soignet SL, Maslak P, Wang Z-G, et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med. 1998;339:1341.

    Article  PubMed  CAS  Google Scholar 

  513. Niu C, Yan H, Yu T, et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: Remission induction, followup, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood. 1999;94:3315.

    PubMed  CAS  Google Scholar 

  514. Huang S-Y, Yang C-H, Chen Y-C. Arsenic trioxide therapy for relapsed acute promyelocytic leukemia: An (sic) useful salvage therapy. Leuk Lymphoma. 2000;38:283.

    Article  CAS  Google Scholar 

  515. Camacho LH, Soignet SL, Chanel S, et al. Leukocytosis and the retinoic acid syndrome in patients with acute promyelocytic leukemia treated with arsenic trioxide. J Clin Oncol. 2000;18:2620.

    PubMed  CAS  Google Scholar 

  516. Lin C-P, Huang M-J, Chang IY, et al. Retinoic acid syndrome induced by arsenic trioxide in treating recurrent all-trans retinoic acid resistant acute promyelocytic leukemia. Leuk Lymphoma. 2000;38:195.

    PubMed  Google Scholar 

  517. Ohnishi K, Yoshida H, Shigeno K, et al. Prolongation of the QT interval and ventricular tachycardia in patients treated with arsenic trioxide for acute promyelocytic leukemia. Ann Intern Med. 2000;133:881.

    PubMed  CAS  Google Scholar 

  518. Unnikrishnan D, Dutcher JP, Varshneya N, et al. Torsades de pointes in 3 patients with leukemia treated with arsenic trioxide. Blood. 2001;97:1514.

    Article  PubMed  CAS  Google Scholar 

  519. Naito K, Kobayashi M, Sahara N, et al. Two cases of acute promyelocytic leukemia complicated by torsade de pointes during arsenic trioxide therapy. Int J Hematol. 2006;83:318–23.

    Article  PubMed  CAS  Google Scholar 

  520. Westervelt P, Brown RA, Adkins DR, et al. Sudden death among patients with acute promyelocytic leukemia treated with arsenic trioxide. Blood. 2001;98:266.

    Article  PubMed  CAS  Google Scholar 

  521. Raghu KG, Yadav GK, Singh R, et al. Evaluation of adverse cardiac events induced by arsenic trioxide, a potent anti-APL drug. J Environ Pathol Toxicol Oncol. 2009;28:241–52.

    Article  PubMed  CAS  Google Scholar 

  522. Kwong YL, Au WY, Chim CS, et al. Arsenic trioxide- and idarubicin-induced remissions in relapsed acute promyelocytic leukemia: Clinicopathological and molecular features of a pilot study. Am J Hematol. 2001;66:274.

    Article  PubMed  CAS  Google Scholar 

  523. Jing Y, Wang L, Xia L, et al. Combined effects of all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia cells in vitro and in vivo. Blood. 2001;97:264.

    Article  PubMed  CAS  Google Scholar 

  524. Muto A, Kizaki M, Kawamura C, et al. A novel differentiation- inducing therapy for acute promyelocytic leukemia with a combination of arsenic trioxide and GM-CSF. Leukemia. 2001;15:1176.

    Article  PubMed  CAS  Google Scholar 

  525. Thirugnanam R, George B, Chendamarai E, et al. Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide-based regimen. Biol Blood Marrow Transplant. 2009;15:1479–84.

    Article  PubMed  CAS  Google Scholar 

  526. Thomas X, Pigneux A, Raffoux E, et al. Superiority of an arsenic trioxide-based regimen over a historic control combining all-trans retinoic acid plus intensive chemotherapy in the treatment of relapsed acute promyelocytic leukemia. Haematologica. 2006;91:996–7.

    PubMed  CAS  Google Scholar 

  527. Shigeno K, Naito K, Sahara N, et al. Arsenic trioxide therapy in relapsed or refractory Japanese patients with acute promyelocytic leukemia: updated outcomes of the phase II study and postremission therapies. Int J Hematol. 2005;82:224–9.

    Article  PubMed  CAS  Google Scholar 

  528. Raffoux E, Rousselot P, Poupon J, et al. Combined treatment with arsenic trioxide and all-trans retinoic acid in patients with relapsed acute promyelocytic leukemia. J Clin Oncol. 2003;21:2326–34.

    Article  PubMed  CAS  Google Scholar 

  529. Lazo G, Kantarjian H, Estey E, et al. Use of arsenic trioxide (As2O3) in the treatment of patients with acute promyelocytic leukemia: the M.D. Anderson experience. Cancer. 2003;97:2218–24.

    Article  PubMed  CAS  Google Scholar 

  530. Visani G, Piccaluga PP, Martinelli G, et al. Sustained molecular remission in advanced acute promyelocytic leukemia with combined pulsed retinoic acid and arsenic trioxide. Clinical evidence of synergistic effect and real-time quantification of minimal residual disease. Haematologica. 2003;88:15.

    Google Scholar 

  531. de Botton S, Fawaz A, Chevret S, et al. Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retrospective analysis of the European acute promyelocytic leukemia group. J Clin Oncol. 2005;23:120–6.

    Article  PubMed  CAS  Google Scholar 

  532. Termuhlen AM, Klopfenstein K, Olshefski R, et al. Mobilization of PML-RARA negative blood stem cells and salvage with autologous peripheral blood stem cell transplantation in children with relapsed acute promyelocytic leukemia. Pediatr Blood Cancer. 2008;51:521–4.

    Article  PubMed  Google Scholar 

  533. Yang D, Hladnik L. Treatment of acute promyelocytic leukemia during pregnancy. Pharmacotherapy. 2009;29:709–24.

    Article  PubMed  Google Scholar 

  534. Ganzitti L, Fachechi G, Driul L, Marchesoni D. Acute promyelocytic leukemia during pregnancy. Fertil Steril. 2010;94(6):2330.

    Article  PubMed  Google Scholar 

  535. Valappil S, Kurkar M, Howell R. Outcome of pregnancy in women treated with all-trans retinoic acid; a case report and review of the literature. Hematology. 2007;12:415–8.

    Article  PubMed  CAS  Google Scholar 

  536. Ammatuna E, Cavaliere A, Divona M, et al. Successful pregnancy after arsenic trioxide therapy for relapsed acute promyelocytic leukaemia. Br J Haematol. 2009;146:341.

    Article  PubMed  Google Scholar 

  537. Hoffman MA, Wiernik PH, Kleiner GJ. Acute promyelocytic leukemia and pregnancy. A case report. Cancer. 1995;76:2237.

    Article  PubMed  CAS  Google Scholar 

  538. Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European Leukemia Net. Blood. 2009;113:1875–91.

    Article  PubMed  CAS  Google Scholar 

  539. Tallman MS, Kwaan HC. Reassessing the hemostatic disorder associated with acute promyelocytic leukemia. Blood. 1992;79:543.

    PubMed  CAS  Google Scholar 

  540. Barbui T, Finazzi G, Falanga A. The impact of all-trans-retinoic acid on the coagulopathy of acute promyelocytic leukemia. Blood. 1998;91:3093.

    PubMed  CAS  Google Scholar 

  541. Gralnick HR, Bagley J, Abrell E. Heparin treatment for the hemorrhagic diathesis of acute promyelocyte leukemia. Am J Med. 1972;52:167.

    Article  PubMed  CAS  Google Scholar 

  542. Jones ME, Saleem A. Acute promyelocytic leukemia: a review of the literature. Am J Med. 1978;65:673.

    Article  PubMed  CAS  Google Scholar 

  543. Cordonnier C, Vernant JP, Brun B, et al. Acute promyelocytic leukemia in 57 previously untreated patients. Cancer. 1985;55:18.

    Article  PubMed  CAS  Google Scholar 

  544. Cunningham I, Gee TS, Reich LM, et al. Acute promyelocytic leukemia: treatment results during a decade at Memorial Hospital. Blood. 1989;72:1116.

    Google Scholar 

  545. Rodeghiero F, Avvisati G, Castaman G, et al. Early deaths and antihemorrhagic treatments in acute promyelocytic leukemia. A GIMEMA retrospective study of 268 consecutive patients. Blood. 1990;75:2112.

    PubMed  CAS  Google Scholar 

  546. Goldberg MA, Ginsburg D, Mayer RJ, et al. Is heparin administration necessary during induction chemotherapy for patients with acute promyelocytic leukemia? Blood. 1987;69:187.

    PubMed  CAS  Google Scholar 

  547. Bennett JM, Young ML, Andersen JW, et al. Long-term survival in acute myeloid leukemia: The Eastern Cooperative Oncology Group Experience. Cancer. 1997;80:2205.

    Article  PubMed  CAS  Google Scholar 

  548. Dombret H, Scrobohaci ML, Zini JM, et al. Coagulation disorders associated with acute promyelocytic leukemia: Corrective effect of all-trans retinoic acid treatment. Leukemia. 1993;7:2.

    PubMed  CAS  Google Scholar 

  549. Watanabe R, Murata M, Takayama N, et al. Long-term follow-up of hemostatic molecular markers during remission induction therapy with all-trans retinoic acid for acute promyelocytic leukemia. Keio Hematology-Oncology Cooperative Study Group (KHOCS). Thromb Haemost. 1997;77:641.

    PubMed  CAS  Google Scholar 

  550. Dombret H, Scrobohaci ML, Daniel MT, et al. In vivo thrombin and plasmin activities in patients with acute promyelocytic leukemia (APL): Effect of all-trans retinoic acid (ATRA) therapy. Leukemia. 1995;9:19.

    PubMed  CAS  Google Scholar 

  551. Tallman MS, Lefẻbvre P, Baine RM, et al. Effects of all-trans retinoic acid or chemotherapy on the molecular regulation of systemic blood coagulation and fibrinolysis in patients with acute promyelocytic leukemia. J Thromb Haemost. 2004;2:1341–50.

    Article  PubMed  CAS  Google Scholar 

  552. Zhang P, Wang SY, Hu XH. Arsenic trioxide treated 72 cases of acute promyelocytic leukemia. Chin J Hematol. 1995;16:26.

    Google Scholar 

  553. Sanz MA, Jarque I, Martin G, et al. Acute promyelocytic leukemia. Therapy results and prognostic factors. Cancer. 1988;61:7.

    Article  PubMed  CAS  Google Scholar 

  554. Fenaux P, Pollet JP, Vandenbossche-Simon L, et al. Treatment of acute promyelocytic leukemia: a report of 70 cases. Leuk Lymphoma. 1990;4:239.

    Article  Google Scholar 

  555. Fenaux P, Tertian G, Castaigne S, et al. A randomized trial of amsacrine and rubidazone in 39 patients with acute promyelocytic leukemia. J Clin Oncol. 1991;9:1556.

    PubMed  CAS  Google Scholar 

  556. Gralnick HR, Sultan C. Acute promyelocytic leukemia: hemorrhagic manifestations and morphologic criteria. Br J Haematol. 1975;29:373.

    Article  PubMed  CAS  Google Scholar 

  557. Groopman J, Ellman L. Acute promyelocytic leukemia. Am J Hematol. 1979;7:395.

    Article  PubMed  CAS  Google Scholar 

  558. Collins AJ, Bloomfield CD, Peterson BA, et al. Acute promyelocytic leukemia: management of the coagulopathy during daunorubicin-prednisone remission induction. Arch Int Med. 1978;138:1677.

    Article  CAS  Google Scholar 

  559. Bennett B, Booth NA, Croll A, Dawson AA. The bleeding disorder in acute promyelocytic leukemia: fibrinolysis due to u-PA rather than defibrination. Br J Haematol. 1989;71:511.

    Article  PubMed  CAS  Google Scholar 

  560. Bennett M, Parker AC, Ludlam CA. Platelet and fibrinogen survival in acute promyelocytic leukemia. Br Med J. 1976;2:565.

    Article  PubMed  CAS  Google Scholar 

  561. Nemerson Y. Tissue factor and hemostasis. Blood. 1988;71:1.

    PubMed  CAS  Google Scholar 

  562. Bauer KA, Conway EM, Bach R, et al. Tissue factor gene expression in acute myeloblastic leukemia. Thromb Res. 1989;50:425.

    Article  Google Scholar 

  563. Andoh K, Sadakata H, Uchiyama T, et al. One-stage method for assay of tissue factor activity of leukemic cells with special reference to disseminated intravascular coagulation. Am J Clin Pathol. 1990;93:679.

    PubMed  CAS  Google Scholar 

  564. Kubota T, Andoh T, Sadakata H, et al. Tissue factor released from leukemic cells. Thromb Haemost. 1991;65:59.

    PubMed  CAS  Google Scholar 

  565. Gordon SG, Franks JJ, Lewis B. Cancer procoagulant A: a factor X activating procoagulant from malignant tissue. Thromb Res. 1975;6:127.

    Article  PubMed  CAS  Google Scholar 

  566. Falanga A, Gordon SG. Isolation and characterization of cancer procoagulant A: a cystine proteinase from malignant tissue. Biochemistry. 1985;24:5558.

    Article  PubMed  CAS  Google Scholar 

  567. Donati MB, Falanga A, Consonni R, et al. Cancer procoagulant in acute nonlymphoid leukemia: relationship of enzyme detection to disease activity. Thromb Haemost. 1990;64:11.

    PubMed  CAS  Google Scholar 

  568. Bevilacqua MP, Pober JS, Majeau GR, et al. Interleukin-1 expression activity of procoagulant activity in human vascular endothelia cells. J Exp Med. 1984;160:618.

    Article  PubMed  CAS  Google Scholar 

  569. Bevilacqua MP, Pober JS, Majeau GR, et al. Recombinant human tissue necrosis factor induces procoagulant activity in cultured human vascular endothelium. Characterization and comparison with interleukin-1. Proc Natl Acad Sci USA. 1986;83:4533.

    Article  PubMed  CAS  Google Scholar 

  570. Nawroth PP, Handley D, Esmon CT, Stern DM. Interleukin-1 induces cell surface anticoagulant activity. Proc Natl Acad Sci USA. 1986;83:3460.

    Article  PubMed  CAS  Google Scholar 

  571. Nawroth PP, Stern MD. Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med. 1986;163:740.

    Article  PubMed  CAS  Google Scholar 

  572. Clauss M, Gerlach M, Gerlach H, et al. Vascular permeability factor: A tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity and promotes monocyte migration. J Exp Med. 1990;172:1535.

    Article  PubMed  CAS  Google Scholar 

  573. Cozzolino F, Torcia M, Miliani A, et al. Potential role of interleukin-1 as the trigger for diffuse intravascular coagulation in acute nonlymphoblastic leukemia. Am J Med. 1988;84:240.

    Article  PubMed  CAS  Google Scholar 

  574. Emeis JJ, Koastra T. Interleukin-1 and lipopolysaccharides induce an inhibitor of plasminogen activator in vivo and in human cultured endothelial cells. J Exp Med. 1986;163:1260.

    Article  PubMed  CAS  Google Scholar 

  575. Nachman RL, Hajjar KA, Silverstein RL, Dinarello CA. Interleukin-1 induces endothelial cell synthesis of plasminogen activator inhibitor. J Exp Med. 1996;163:1595.

    Article  Google Scholar 

  576. Miyauchi S, Morohama T, Kyoizumi S, et al. Malignant tumor cell lines produce interleukin-1-like factor in vivo. In Vitro Cell Dev Biol. 1988;24:753.

    Article  PubMed  CAS  Google Scholar 

  577. Noguchi M, Sakai T, Kisiel W. Identification and partial purification of novel tumor-derived protein that induces tissue factor in cultured human endothelial cells. Biochem Biophys Res Commun. 1989;160:222.

    Article  PubMed  CAS  Google Scholar 

  578. Chan TK, Chan GT, Chan V. Hypofibrinogenemia due to increased fibrinolysis in two patients with acute promyelocytic leukemia. Aust NZ J Med. 1984;14:245.

    Article  CAS  Google Scholar 

  579. Sterrenberg L, Haak HL, Brommer EJP, Nieuwenhuizen W. Evidence of fibrinogen breakdown by leukocyte enzymes in a patient with acute promyelocytic leukemia. Haemostasis. 1985;15:126.

    PubMed  CAS  Google Scholar 

  580. Schwartz BS, Williams EC, Conlan MG, Mosher DF. Epsilon-aminocaproic acid in the treatment of patients with acute promyelocytic leukemia and acquired alpha-2-plasmin inhibitor deficiency. Ann Intern Med. 1986;105:873.

    PubMed  CAS  Google Scholar 

  581. Velasco F, Torres A, Andres P, et al. Changes in plasma levels of protease and fibrinolytic inhibitors induced by treatment of acute promyelocytic leukemia. Thromb Haemost. 1984;52:81.

    PubMed  CAS  Google Scholar 

  582. Wilson EL, Jacobs P, Dowdle EB. The secretion of plasminogen activators by human myeloid leukemia cells in vitro. Blood. 1983;61:568.

    PubMed  CAS  Google Scholar 

  583. Sakata Y, Murakami T, Noro A, et al. The specific activity of plasminogen activator inhibitor-1 in disseminated intravascular coagulation with acute promyelocytic leukemia. Blood. 1991;77:1949.

    PubMed  CAS  Google Scholar 

  584. Hirata F, Schiffman E, Venkatasubramanian K, et al. A phospholipase A2 inhibitory protein in rabbit neutrophils induced by glucocorticoids. Proc Natl Acad Sci USA. 1980;77:2533.

    Article  PubMed  CAS  Google Scholar 

  585. Chang KS, Wang G, Freireich EJ, et al. Specific expression of the annexin VIII gene in acute promyelocytic leukemia. Blood. 1992;79:1802.

    PubMed  CAS  Google Scholar 

  586. Hajjar KA, Jacovina AT, Chacko J. An endothelial cell receptor for plasminogen/tissue plasminogen activator. I. Identity with annexin II. J Biol Chem. 1994;269:21191.

    PubMed  CAS  Google Scholar 

  587. Menell JS, Cesarman GM, Jacovina AT, et al. Annexin II and bleeding in acute promyelocytic leukemia. N Engl J Med. 1999;340:994.

    Article  PubMed  CAS  Google Scholar 

  588. Federici AR, Diamico EA. The role of von Willebrand factor in the hemostatic defect of acute promyelocytic leukemia. Leuk Lymphoma. 1998;31:491.

    PubMed  CAS  Google Scholar 

  589. Runde V, Aul C, Heyll A, Schneider W. All-trans retinoic acid: not only a differentiating agent, but also an inducer of thromboembolic events in patients with M3 leukemia. Blood. 1992;79:534.

    PubMed  CAS  Google Scholar 

  590. Escudier SM, Kantarjian HM, Estey EH. Thrombosis in patients with acute promyelocytic leukemia treated with and without alltrans retinoic acid. Leuk Lymphoma. 1996;20:435.

    Article  PubMed  CAS  Google Scholar 

  591. Hashimoto S, Koike T, Tatewaki W, et al. Fatal thromboembolism in acute promyelocytic leukemia during all-trans retinoic acid therapy combined with antifibrinolytic therapy as prophylaxis of hemorrhage. Leukemia. 1994;8:1113.

    PubMed  CAS  Google Scholar 

  592. Ishii H, Horie S, Kizaki K, Kazama M. Retinoic acid counteracts both the down-regulation of thrombomodulin and the induction of tissue factor in cultured human endothelial cells exposed to tumor necrosis factor. Blood. 1992;80:2556.

    PubMed  CAS  Google Scholar 

  593. Rickles FR, Hair G, Schmeizel M, et al. All-trans-retinoic (ATRA) inhibits the expression of tissue factor in human progranulocytic. (Abstr). Haemost Thromb. 1993;69:107.

    Google Scholar 

  594. Falanga A, Iacoviello L, Evangelista V, et al. Loss of blast cell procoagulant activity and improvement of hemostatic variables in patients with acute promyelocytic leukemia administered alltrans-retinoic acid. Blood. 1995;86:1072.

    PubMed  CAS  Google Scholar 

  595. De Stefano V, Teofili L, Sica S, et al. Effect of all-trans retinoic acid on procoagulant and fibrinolytic activities of cultured blast cells from patients with acute promyelocytic leukemia. Blood. 1995;86:3535.

    PubMed  Google Scholar 

  596. Medh R, Santell L, Levin EG. Stimulation of tissue plasminogen activator production by retinoic acid: Synergistic effect on protein kinase c-mediated activation. Blood. 1992;80:981.

    PubMed  CAS  Google Scholar 

  597. Lansink M, Kooistra T. Stimulation of tissue-type plasminogen activator expression by retinoic acid in human endothelial cells retinoic acid receptor β2 induction. Blood. 1996;88:531.

    PubMed  CAS  Google Scholar 

  598. Falanga A, Consom R, Marchetti M, et al. Cancer procoagulant in the human promyelocytic cell line NB4 and its modulation by alltrans retinoic acid. Leukemia. 1994;8:156.

    PubMed  CAS  Google Scholar 

  599. Tallman MS, Lefebrvre P, Cohen I, et al. Procoagulant, profibrinolytic and proinflammatory mediators in patients with previously untreated acute promyelocytic leukemia (APL). (Abstr). Blood. 1995;86:675.

    Google Scholar 

  600. Burnett AK, Goldstone AH, Gray RG, Wheatley K. All trans retinoic acid given concurrently with induction chemotherapy improves the outcome of APL: Results of the UK MRC ATRA trial. (Abstr). Blood. 1997;90:1474.

    Google Scholar 

  601. Avvisati G. AIDA protocol: the Italian way of treating APL (Abstr). Br J Haematol. 1998;102:593.

    Google Scholar 

  602. Asou N, Adachi K, Tamura J, et al. Analysis of prognostic factors in newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. J Clin Oncol. 1998;16:78.

    PubMed  CAS  Google Scholar 

  603. Sanz MA, Martin G, Rayon C, et al. A modified AIDA protocol with anthracycline-based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/RAR-alpha-positive acute promyelocytic leukemia. Blood. 1999;94:3015.

    PubMed  CAS  Google Scholar 

  604. Zhu J, Guo WM, Yao YY, et al. Tissue factors on acute promyelocytic leukemia and endothelial cells are differently regulated by retinoic acid, arsenic trioxide and chemotherapeutic agents. Leukemia. 1999;13:1062.

    Article  PubMed  CAS  Google Scholar 

  605. Sanz MA, Montesinos P. Open issues on bleeding and thrombosis in acute promyelocytic leukemia. Thromb Res. 2010;125 Suppl 2:S51–4.

    Article  PubMed  Google Scholar 

  606. Slack JL, Rusiniak ME. Current issues in the management of acute promyelocytic leukemia. Ann Hematol. 2000;79:227.

    Article  PubMed  CAS  Google Scholar 

  607. Avvisati G, Lo Coco F, Mandelli F. Acute promyelocytic leukemia: clinical and morphologic features and prognostic factors. Semin Hematol. 2001;38:4.

    Article  PubMed  CAS  Google Scholar 

  608. Fenaux P, Chomienne C, Degos L. All-trans retinoic acid and chemotherapy in the treatment of acute promyelocytic leukemia. Semin Hematol. 2001;38:13.

    Article  PubMed  CAS  Google Scholar 

  609. Lo-Coco F, Avvisati G, Vignetti M, 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. 2010;116(17):3171–9.

    Article  PubMed  CAS  Google Scholar 

  610. Xiang Y, Wang XB, Sun SJ, et al. Compound huangdai tablet as induction therapy for 193 patients with acute promyelocytic leukemia. Zhonghua Xue Ye Xue Za Zhi. 2009;30:440–2.

    PubMed  Google Scholar 

  611. Furugaki K, Pokorna K, Le Pogam C, et al. DNA vaccination with all-trans retinoic acid treatment induces long-term survival and elicits specific immune responses requiring CD4+ and CD8+ T-cell activation in an acute promyelocytic leukemia mouse model. Blood. 2010;115:653–6.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Peter H. Wiernik M.D. .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Wiernik, P.H., Gallagher, R.E., Tallman, M.S. (2013). Acute Promyelocytic Leukemia. In: Wiernik, P., Goldman, J., Dutcher, J., Kyle, R. (eds) Neoplastic Diseases of the Blood. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3764-2_23

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-3764-2_23

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4614-3763-5

  • Online ISBN: 978-1-4614-3764-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics