Leukemogenesis and therapy of acute promyelocytic leukemia: from the worse to the most favorable subtype of acute myeloid leukemia

1. Hillestad LK. Acute promyelocytic leukemia. Acta Med Scand 1957; 159: 189–194.

2. Golomb HM, Rowley JD, Vardiman J et al. Partial deletion of long arm of chromosome 17: a specific abnormity in acute promyelocytic leukemia? Arch Intern Med 1976; 136: 825–828.

3. Rowley JD, Golomb HM, Dougherty C. 15/17 Translocation: a consistent chromosomal change in acute promyelocytic leukemia. Lancet 1977; 1: 549–550.

4. 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: 827–841.

5. Mattei MG, Petkovich M, Mattei JF et al. Mapping of the human retinoic acid receptor to the q21 band of chromosome 17. Hum Genet 1988; 80: 186–188.

6. de The H, Chomienne C, Lanotte M et al. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature 1990; 347: 558–561.

7. Borrow J, Goddard AD, Sheer D et al. Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17. Science 1990; 249: 1577–1580.

8. Goddard AD, Borrow J, Freemont P et al. Characterization of a zinc finger gene disrupted by the t(15;17) in acute promyelocytic leukemia. Science 1991; 254: 1371–1374.

9. Umesono K, Murakami KK, Thompson CC et al. Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors. Cell 1991; 65: 1255–1266.

10. Melnick A, Licht JD. Deconstructing a disease: RARα, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 1999; 93: 3167–3215.

11. Chen JD, Evans RM. A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 1995; 377: 454–457.

12. Pazin MJ, Kadonaga JT. What’s up and down with histone deacetylation and transcription? Cell 1997; 89: 325–328.

13. Bannister AJ, Kouzarides T. The CBP co-activator is a histone acetyltransferase. Nature 1996; 348: 641–643.

14. Chen H, Lin RJ, Schiltz RL et al. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 1997; 90: 569–580.

15. Chen Z, Brand NJ, Chen A et al. Fusion between a novel Krüppel‑like zinc finger gene and the retinoic acid receptor-α locus due to a variant t(11;17) translocation associated with acute promyelocytic leukaemia. EMBO J 1993; 12: 1161–1167.

16. Wells RA, Kamel-Reid S. NuMA-RARA, a new gene fusion in acute promyelocytic leukaemia. Blood 1996; 88: 365a.

17. Redner RL, Rush EA, Faas S et al. The t(5;17) variant of acute promyelocytic leukemia expresses a nucleophosmin – retinoic acid receptor fusion. Blood 1996; 87: 882–886.

18. Arnould C, Philippe C, Bourdon V et al. The signal transducer and activator of transcription STAT5b gene is a new partner of retinoic acid receptor α in acute promyelocytic‑like leukemia. Hum Mol Genet 1999; 8: 1741–1749.

19. Catalano A, Dawson MA, Somana K et al. The PRKAR1A gene is fused to RARA in a new variant acute promyelocytic leukemia. Blood 2007; 110: 4073–4076.

20. Guidez F, Ivins S, Zhu J et al. Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML‑ and PLZF-RARα underlie molecular pathogenesis and treatment of acute promyelocytic leukemia. Blood 1998; 91: 2634–2642.

21. Gambacorta M, Flenghi L, Fagioli M et al. Heterogeneous nuclear expression of the promyelocytic leukemia (PML) protein in normal and neoplastic human tissues. Am J Pathol 1996; 149: 2023–2035.

22. Lam YW, Ammerlaan W, O WS et al. Cell type- and differentiation stage-dependent expression of PML domains in rat, detected by monoclonal antibody HIS55. Exp Cell Res 1995; 221: 344–356.

23. Wang ZG, Delva L, Gaboli M et al. Role of PML in cell growth and the retinoic acid pathway. Science 1998; 279: 1547–1551.

24. Salomoni P, Pandolfi PP. The role of PML in tumor suppression. Cell 2002; 108: 165–170.

25. Grisolano JL, Wesselschmidt RL, Pelicci PG et al. Altered myeloid development and acute leukemia in transgenic mice expressing PML‑RAR alpha under control of cathepsin G regulatory sequences. Blood 1997; 89: 376–387.

26. Klemsz MJ, McKercher SJ, Celada A et al. The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene. Cell 1990; 61: 113–124.

27. Fisher RC, Scott EW. Role of PU.1 in hematopoiesis. Stem Cells 1998; 16: 25–37.

28. Lekstrom-Himes JA. The role of C/EBPε in the terminal stages of granulocyte differentiation. Stem Cells 2001; 19: 125–133.

29. Metcalf D, Dakic A, Mifsud S et al. Inactivation of PU.1 in adult mice leads to the development of myeloid leukemia. Proc Natl Acad Sci USA 2006; 103: 1486–1491.

30. Dakic A, Metcalf D, Di Rago L et al. PU.1 regulates the commitment of adult hematopoietic progenitors and restricts granulopoiesis. J Exp Med 2005; 201: 1487–1502.

31. Walter MJ, Park JS, Ries RE et al. Reduced PU.1 expression causes myeloid progenitor expansion and increased leukemia penetrance in mice expressing PML‑RARα. Proc Natl Acad Sci USA 2005; 102: 12513–12518.

32. Mueller BU, Pabst T, Fos J et al. ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression. Blood 2006; 107: 3330–3338.

33. Didisheim P, Trombold JS, Vandervoort RLE et al. Acute promyelocytic leukemia with fibrinogen and factor V deficiencies. Blood 1964; 23: 717–728.

34. Bernard J, Weil M, Boiron M et al. Acute promyelocytic leukemia: results of treatment by daunorubicin. Blood 1973; 41: 489–496.

35. Cunningham I, Gee TS, Reich LM et al. Acute promyelocytic leukemia: treatment results during a decade at Memorial Hospital. Blood 1989; 73: 1116–1122.

36. Cordonnier C, Vernant JP, Brun B et al. Acute promyelocytic leukemia in 58 previously untreated patients. Cancer 1985; 55: 18–25.

37. Daly PA, Schiffer CA, Wiernik PH. Acute promyelocytic leukemia – Clinical management of 15 patients. Am J Hematol 1980; 8: 347–359.

38. Collins AJ, Bloomfield CD, Peterson BS et al. Acute promyelocytic leukemia. Management of the coagulopathy during daunorubicine-prednisone remission induction. Arch Intern Med 1978; 138: 1677–1680.

39. Bennett JM, Begg CB. Eastern Cooperative Oncology Group study of the cytochemistry of adult acute myeloid leukemia by correlation of subtypes with response and survival. Cancer Res 1981; 41: 4833–4837.

40. Hurd DD, Vukelich M, Artur DC et al. 15;17 translocation in acute promyelocytic leukemia. Cancer Genet Cytogenet 1982; 6: 331–337.

41. Cassileth PA, Begg CB, Bennett JM et al. A randomized study of the efficacy of consolidation therapy in adult nonlymphocytic leukemia. Blood 1984; 63: 843–847.

42. Kantarjian HM, Keating MJ, McCredie G et al. Acute promyelocytic leukemia: The M.D. Anderson Hospital experience. Am J Med 1986; 80: 789–797.

43. Ruggero D, Baccarani M, Guarini A et al. Acute promyelocytic leukemia: Results of therapy and analysis of 13 cases. Acta Haematol 1977; 58: 108–119.

44. Rai KR, Holland JF, Glidewell OJ et al. Treatment of acute myelocytic leukemia: A study by cancer and leukemia group B. Blood 1981; 58: 1203–1212.

45. Weinstein HJ, Mayer RJ, Rosenthal DS et al. Chemotherapy for acute myelogenous leukemia in children and adults: VAPA update. Blood 1983; 62: 315–319.

46. Goldberg MA, Ginsburg D, Mayer RJ et al. Is heparin administration necessary during induction chemotherapy for patients with acute promyelocytic leukemia? Blood 1987; 69: 187–191.

47. Fujimaki Y. Formation of carcinoma in albino rats fed on deficient diets. J Cancer Res 1926; 10: 469–477.

48. Wolbach SB, Howe PR. Tissue changes following deprivation of fat soluble A vitamin. J Exp Med 1925; 42: 753–777.

49. Wolbach SB, Howe PR. Vitamin A deficiency in guinea pig. Arch Pathol Lab Med 1928; 5: 239–253.

50. Bollag W. Prophylaxis of chemically induced benign and malignant epithelial tumors by vitamin A acid (retinoid acid). Eur J Cancer 1972; 8: 689–693.

51. Sporn MB, Square RA, Brown CC et al. 13-cis‑retinoic acid: inhibition of bladder carcinogenesis in the rat. Science 1977; 195: 487–489.

52. Hodges R, Sauberlich H, Canham J et al. Hematopoietic studies in Vitamin A deficienty. Am J Clin Nutr 1978; 31: 876–885.

53. Collins SJ, Gallo RC, Gallagher RE. Continuous growth and differentiation of human myeloid leukaemic cells in suspension culture. Nature 1977; 270: 347–349.

54. Collins SJ, Ruscetti FW, Gallagher RE et al. Terminal differentiation of human promyelocytic leukemia cells induced by dimethyl sulfoxide and other polar compounds. Proc Natl Acad Sci USA 1978; 75: 2458–2462.

55. Breitman TR, Selonick SE, Collins SJ. Induction of differentiation of the human promyelocytic leukemia cell line (HL‑60) by retinoid acid. Proc Natl Acad Sci USA 1980; 77: 2936–2940.

56. Heller EH, Shiffman NJ. Syntetic retinoids in dermatology. Can Med Assoc J 1985; 132: 1129–1136.

57. Flynn PJ, Miller WJ, Weisdorf DJ et al. Retinoic acid treatment of acute promyelocytic leukemia: in vitro and in vivo observation. Blood 1983; 62: 1211–1217.

58. Nilsson B. Probable in vivo induction of differentiation by retinoid acid of promyelocytes in acute promyelocytic leukemia. Br J Haematol 1984; 57: 365–371.

59. Fontana JA, Rogers JS, Durham JP. The role of 13-cis‑retinoic acid in the remission induction of a patient with acute promyelocytic leukemia. Cancer 1986; 57: 209–217.

60. Daenen S, Vellenga E, van Dobbenburgh OA et al. Retinoic acid as antileukemic therapy in a patient with acute promyelocytic leukemia and Aspergillus pneumonia. Blood 1986; 67: 559–561.

61. Sampi K, Honma Y, Hozumi M et al. Discrepancy between in-vitro and in-vivo inductions of differentiation by retinoids of human acute promyelocytic leukemia cells in relapse. Leuk Res 1985; 9: 1475–1478.

62. Chomienne C, Ballerini P, Balitrand N et al. All-trans retinoic acid in acute promyelocytic leukemias: II. In vitro studies: structure-function relationship. Blood 1990; 76: 1710–1717.

63. Chomienne C, Ballerini P, Balitrand N et al. Retinoic acid therapy for promyelocytic leukaemia. Lancet 1989; 2: 746–747.

64. Windhorst DB, Nigra T. General clinical toxicity of oral retinoids. J Am Acad Dermatol 1982; 6: 675–682.

65. Cullum ME, Zile MH. Metabolism of all‑trans‑retinoic acid and all‑trans‑retinyl acetate. Demonstration of common physiological metabolites in rat small intestinal mucosa and circulation. J Biol Chem 1985; 260: 10590–10596.

66. Huang ME, Ye YC, Chen SR et al. Use of all‑trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988; 72: 567–572.

67. Chen ZX, Xue YQ, Zhang R et al. A clinical and experimental study on all‑trans retinoic acid-treated acute promyelocytic leukemia patients. Blood 1991; 78: 1413–1419.

68. Castaigne S, Chomienne C, Daniel MT et al. All-trans retinoic acid as a dif-ferentiation therapy to acute promyelocytic leukemia. I. Clinical Results. Blood 1990; 76: 1704–1709.

69. Fenaux P, Castaigne S, Dombret H et al. All-transretinoic acid followed by intensive chemotherapy gives a high complete remission rate and may prolong remission in newly diagnosed acute promyelocytic leukemia: a pilot study on 26 cases. Blood 1992; 80: 2176–2181.

70. Warrell RP Jr, Frankel R, Miller WH Jr et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all trans retinoic acid). N Engl J Med 1991; 324: 1385–1393.

71. Fenaux P, Le Deley MC, Castaigne S et al. Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia. Results of a multicenter randomized trial. European APL 91 Group. Blood 1993; 82: 3241–3249.

72. Fenaux P, Chastang C, Chevret S et al. A randomized comparison of all trans-retinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. Blood 1999; 94: 1192–1200.

73. Vahdat L, Maslak P, Miller WH et al. Early mortality and the retinoic acid syndrome in acute promyelocytic leukemias: Impact of leukocytosis, low-dose chemotherapy, PMN/RARAα isoform, and CD13 expression in patients treated with all‑trans retinoic acid. Blood 1994; 84: 3843–3849.

74. Bourgeois E, Chevret S, Sanz M et al. Long term follow up of APL treated with ATRA and chemotherapy (CT) including incidence of late relapses and overall toxicity. Blood 2003; 102: 140a, (Abstract 483).

75. Frankel SR, Eardley A, Heller G et al. All-trans retinoic acid for acute promyelocytic leukemia. Results of the New York study. Ann Intern Med 1994; 120: 278–286.

76. Tallman MS, Andersen JW, Schiffer CA et al. All-trans‑retinoic acid in acute promyelocytic leukemia. N Engl J Med 1997; 337: 1021–1028.

77. Tallman MS, Andersen JW, Schiffer CA et al. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 2002; 100: 4298–4302.

78. Kanamaru A, Takemoto Y, Tanimoto M et al. All-trans retinoic acid for the treatment of newly diagnosed acute promyelocytic leukemia. Japan Adult Leukemia Study Group Blood 1995; 85: 1202–1206.

79. Head D, Kopecky KJ, Weick J et al. Effect of agressive daunorubicine therapy on survival in acute promyelocytic leukemia. Blood 1995; 86: 1717–1728.

80. Avvisati G, Mandelli F, Petti MC et al. Idarubicin (4-demethoxydaunorubicin) as 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: 257–260.

81. 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 of minimal follow‑up. Blood 2002; 100: 3141–3146.

82. Testi AM, Biondi A, Lo Coco F et al. GIMEMA-AIEOP AIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children. Blood 2005; 106: 447–453.

83. Avvisati 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 dell’Adulto (GIMEMA) pilot study. Blood 1996; 88: 1390–1398.

84. 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. Blood 1997; 90: 1014–1021.

85. Avvisati G, Petti MC, Lo Coco F et al. AIDA: The Italian way of treating acute promyelocytic leukemia (APL). Final act. Blood 2003; 102: 104a (Abstract 487).

86. Schwarz J, Lemež P, Lukášová M et al. High incidence of thromboembolic events in leukemic patients with acute promyelocytic leukemia (APL). Blood 1996; 88: 169b (Abstract 3404).

87. Baker WG, Bang NU, Nachman RL et al. Hypofibrinogenemic hemorrhage in acute myelogenous leukemia treated with heparin. With autopsy findings of widespread intravascular clotting. Ann Intern Med 1964; 61: 116–123.

88. Testi AM, Lo Coco F, Biondi A et al. GIMEMA-AIEOP AIDA protocol for the treatment of newly diagnosed acute promyelocytic leukemia (APL) in children. Blood 2003; 102: 141a (Abstract 485).

89. 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 randomized MRC trial. Blood 1999; 93: 4131–4143.

90. 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. German AML Cooperative Group. Leukemia 2000; 14: 1362–1370.

91. Sanz MA, Martín G, Rayón C et al. A modified AIDA protocol with anthracycline‑based consolidation results in high antileukemic eficacy and reduced toxicity in newly diagnosed PML/RARα-positive acute promyelocytic leukemia. Blood 1999; 94: 3015–3021.

92. Sanz MA, Martín G, Gonzáles M et al. Risk-adapted treatment of acute promyelocytic leukemia with all‑trans‑retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood 2004; 103: 1237–1243.

93. Adés 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: 5703–5710.

94. Warrell RP Jr. Retinoid resistance in acute promyelocytic leukemia: new mechanisms, strategies, and implications. Blood 1993; 82: 1949–1953.

95. Gallagher RE. Retinoic acid resistance in acute promyelocytic leukemia. Leukemia 2002; 16: 1940–1958.

96. Zhou DC, Hallam SJ, Lee SJ et al. 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: 5770–5776.

97. Fiorella PD, Napoli JL. Expression of cellular retinoic acid binding protein (CRABP) in Escherichia coli. Characterization and evidence that holo-CRABP is a substrate in retinoic acid metabolism. J Biol Chem 1991; 266: 16572–16579.

98. Cornic M, Delva L, Guidez F et al. 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: 3329–3334.

99. Delva L, Cornic M, Balitrand N et al. Resistance to all‑trans retinoic acid (ATRA) therapy in relapsing acute promyelocytic leukemia: study of in vitro ATRA sensitivity and cellular retinoic acid binding protein levels in leukemic cells. Blood 1993; 82: 2175–2181.

100. Muindi JF, Young CW. Lipid hydroperoxides greatly increase the rate of oxidative catabolism of all‑trans‑retinoic acid by human cell culture microsomes genetically enriched in specified cytochrome P-450 isoforms. Cancer Res 1993; 53: 1226–1229.

101. Muindi J, Frankel SR, Miller WH Jr 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.

102. Adamson PC, Boylan JF, Balis FM et al. Time course of induction of metabolism of all‑trans‑retinoic acid and the up-regulation of cellular retinoic acid-binding protein. Cancer Res 1993; 53: 472–476.

103. Drach J, Lopez-Berestein G, McQueen G et al. Induction of differentiation in myeloid leukemia cell lines and acute pomyelocytic leukemia cells by liposomal all‑trans‑retinoic acid. Cancer Res 1993; 53: 2100–2104.

104. 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: 73–80.

105. Estey EH, Giles FJ, Kantarjian H et al. Molecular remissions induced by liposomal-encapsulated all‑trans retinoic acid in newly diagnosed acute promyelocytic leukemia. Blood 1999; 94: 2230–2235.

106. Tsimberidou AM, Tirado-Go-mez M, Andreeff M et al. Single-agent liposomal all‑trans retinoic acid can cure some patients with untreated acute promyelocytic leukemia: an update of The University of Texas M.D. Anderson Cancer Center Series. Leuk Lymphoma 2006; 47: 1062–1068.

107. Zhou DC, Kim SH, Ding W et al. Frequent mutations in the ligand-binding domain of PML‑RARα after multiple relapses of acute promyelocytic leukemia: analysis for functional relationship to response to all‑trans retinoic acid and histone deacetylase inhibitors in vitro and in vivo. Blood 2002; 99: 1356–1363.

108. Marasca R, Zucchini P, Galimberti S et al. Missense mutations in the PML/RARα ligand binding domain in ATRA-resistant As(2)O(3) sensitive relapsed acute promyelocytic leukemia. Haematologica 1999; 84: 963–968.

109. Marasca R, Zucchini P, Iannitelli P et al. PML/RAR alpha mutations in relapsed acute promyelocytic leukemia. Joint International Congress on APL and Differentiation therapy 2001 (Abstract 34).

110. Ding W, Li YP, Nobile LM et al. Leukemic cellular retinoic acid resistance and missense mutations in the PML‑RARα fusion gene after relapse of acute promyelocytic leukemia from treatment with all‑trans retinoid acid and intensive chemotherapy. Blood 1998; 92: 1172–1183.

111. Imaizumi M, Suzuki H, Yoshinari M et al. Mutations in the E-domain of RARα portion of the PML/RARα chimeric gene may confer clinical resistance to all‑trans retinoic acid in acute promyelocytic leukemia. Blood 1998; 92: 374–382.

112. Côté S, Rosenauer A, Bianchini A et al. Response to histone deacetylase inhibition of novel PML/RARα mutants detected in retinoic acid-resistant APL cells. Blood 2002; 100: 2586–2596.

113. Takayama N, Kizaki M, Hida T et al. Novel mutation in the PML/RARα chimeric gene exhibits dramatically decreased ligand-binding activity and confers aquired resistence to retinoic acid in acute promyelocytic leukemia. Exp Hematol 2001; 29: 864–872.

114. Nason-Burchenal K, Allopenna J, Begue A et al. Targeting of PML/RARα is lethal to retinoic acid-resistant promyelocytic leukemia cells. Blood 1998; 92: 1758–1767.

115. Shao W, Benedetti L, Lamph WW et al. A retinoid-resistant acute promyelocytic leukemia subclone expresses a dominant negative PML‑RAR alpha mutation. Blood 1997; 89: 4282–4289.

116. Kitamura K, Kiyoi H, Yoshida H et al. Mutant AF-2 domain of PML‑RARα in retinoic acid-resistant NB4 cells: differentiation induced by RA is triggered directly through PML‑RARα and its down-regulation in acute promyelocytic leukemia. Leukemia 1997; 11: 1950–1956.

117. Dupres E, Benoit G, Flexor M et al. A mutated PML/RARA found in the retinoid maturation resistant NB4 subclone, NB4-R2, blocks RARA and wild-type PML/RARA transcriptional activities. Leukemia 2000; 14: 255–261.

118. Zhang TD, Chen GQ, Wang ZG et al. Arsenic trioxide, a therapeutic agent for APL. Oncogene 2001; 20: 7146–7153.

119. Lissauer H. Zwei Fälle von Leukämie. Berl Klin Wochenschr 1865; 2: 403–404.

120. Conrad ME. Treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 1999; 340: 1044–1045.

121. Kwong YL, Todd D. Delicious Poison: Arsenic trioxide for the treatment of leukemia. Blood 1997; 89: 3487–3487.

122. Forkner CE, Scott TFM. Arsenic as a therapeutic agent in chronic myelogenous leukemia. JAMA 1931; 97: 3–5.

123. Zhou GB, Zhao WL, Wang ZY et al. Retinoic acid and arsenic for treating acute promyelocytic leukemia. PLoS Med 2005; 2: e12.

124. 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: 3354–3360.

125. Soignet SL, Maslak P, Wang ZG et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 1998; 339: 1341–1348.

126. Soignet SL. Clinical experience of arsenic trioxide in relapsed acute promyelocytic leukemia. Oncologist 2001; 6: 11–16.

127. Soignet SL, Frankel SR, Douer D et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001; 19: 3852–3860.

128. Douer D, Hu W, Giralt S et al. Arsenic trioxide (trisenox) therapy for acute promyelocytic leukemia in the setting of hematopoietic stem cell transplantation. Oncologist 2003; 8: 132–140.

129. Niu C, Yan H, Yu T et al. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow‑up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood 1999; 94: 3315–3324.

130. Mathews V, George B, Lakshmi KM et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood 2006; 107: 2627–2632.

131. Singer JW, Kirkhart B, Frank K et al. Safety with Trisenox (arsenic trioxide). Blood 2003; 102: 11. Abstract 5767.

132. Estey E, Garcia-Manero G, Ferra-joli A et al. Use of all‑trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood 2006; 107: 3469–3473.

133. Sanz MA, Vellenga E, Rayón C et al. All-trans retinoic acid and anthracycline monochemotherapy for the treatment of elderly patients with acute promyelocytic leukemia. Blood 2004; 104: 3490–3493.

134. Ades L, Chevret S, De Botton S et al. Outcome of acute promyelocytic leukemia treated with all trans retinoic acid and chemotherapy in elderly patients: the European group experience. Leukemia 2005; 19: 230–233.

135. Powell BL. Effect of consolidation with arsenic trioxide (As2O3) on event-free survival (EFS) and overall survival (OS) among patients with newly diagnosed acute promyelocytic leukemia (APL): North American Intergroup Protocol C9710. J Clin Oncol 2007; 25: 5143–5150.

136. Chen GQ, Shi XG, Tang W 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: 3345–3353.

137. Pan XY, Chen GQ, Cai L et al. Anion exchanger 2 mediates the action of arsenic trioxide. Br J Haematol 2006; 134: 491–499.

138. Jennette KW. The role of metals in carcinogenesis: biochemistry and metabolism. Environ Health Perspect 1981; 40: 233–252.

139. Chen GQ, Zhu J, Shi XG et al. In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia: As2O3 induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML‑RAR alpha/PML proteins. Blood 1996; 88: 1052–1061.

140. Chen Z, Chen GQ, Shen ZX et al. Treatment of acute promyelocytic leukemia with arsenic compounds: in vitro and in vivo studies. Semin Hematol 2001; 38: 26–36.

141. Davison K, Mann KK, Miller WH Jr. Arsenic trioxide: Mechanisms of action. Semin Hematol 2002; 39: 3–7.

142. Huang C, Ma W, Li J et al. Arsenic induces apoptosis through a c-Jun NH2-terminal kinase-dependent, p53-in-dependent pathway. Cancer Res 1999; 59: 3053–3058.

143. De Thé H, Chelbi-Alix MK. APL, a model disease for cancer therapies? Oncogene 2001; 20: 7136–7139.

144. Lallemand-Breitenbach V, Zhu J, Puvion F 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: 1361–1371.

145. Mann KK, Padovani AMS, Guo Q et al. Arsenic trioxide inhibits nuclear receptor function via SEK1/JNK–mediated RXRα phosphorylation. J Clin Invest 2005; 115: 2924–2933.

146. Jing Y, Wang L, Xia L 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: 264–269.

147. Zhang P, Wang SY, Hu XH et al. Arsenic trioxide-treated 72 cases of acute promyelocytic leukemia. Chin J Hematol 1996; 17: 170–171.

148. De Botton S, Chevret S, Sanz M et al. Additional chromosomal abnor--malities have no effect on the clinical outcome of patients with acute promyelocytic leu-kemia. Br J Haematol 2000; 111: 801–806.

149. Cervera J, Martín G, Hernández JM et al. Additional chromosome abnormalities have no prognostic value in acute promyelocytic leukemia patiens treated with simultaneous ATRA and anthracycline‑based chemotherapy: an update of the LPA96 and LPA99 PETHEMA protocols. Blood 2004; 104: 2019.

150. Hernández JM, Martín G, Gutiérrez NC et al. Additional cytogenetic changes do not influence the outcome of patients with newly diagnose acute promyelocytic leukemia treated with an ATRA plus an-thracyclin based protocol. A report of the Spanish group PETHEMA. Haematologica 2001; 86: 807–813.

151. Gilliland DG, Griffin JD. The roles of FLT3 in hematopoiesis and leukemia. Blood 2002; 100: 1532–1542.

152. Molineaux G, McCrea C, Yan XQ et al. Flt-3 ligand synergizes with granulocyty colony-stimulating factor to increase neutrophil numbers and to mobilize peripheral blood stem cells with long–term repopulating potential. Blood 1997; 89: 3998–4004.

153. Yamamoto Y, Kioyoi H, Nakano Y et al. Activating mutation of D835 within the activation loop of FLT3 in human hematological malignancies. Blood 2001; 97: 2434–2439.

154. Kiyoi H, Towatari M, Kokota S et al. Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia 1998; 12: 1333–1337.

155. Rombouts WJC, Blokland I, Löwenberg B et al. Biological characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplications in the FLT3 gene. Leukemia 2000; 14: 675–683.

156. Schnittger S, Schoch C, Dugas M et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 2002; 100: 59–66.

157. Thiede C, Steudel C, Mohr B et al. Analysis of FLT3-activationg mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002; 99: 4326–4335.

158. Callens C, Chevret S, Cayuela JM 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: 1153–1160.

159. Kiyoi H, Naoe T, Yokota S et al. Internal tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia: Leukemia Study Group of the Ministry of Health and Welfare (Kohseisho). Leukemia 1997; 11: 1447–1452.

160. Au WY, Fung A, Chim CS et al. FLT-3 aberrations in acute promyelocytic leukemia: clinicopathological associations and prognostic impact. Br J Haematol 2004; 125: 463–469.

161. Kottaridis PD, Gale RE, Langabeer SE et al. Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors. Blood 2002; 100: 2393–2398.

162. Gale RE, Hilus R, Pizzey AR et al. Relationship between FLT3 mutation status, biologic characteristics, and response to targeted therapy in acute promyelocytic leukemia. Blood 2005; 106: 3768–3776.

163. Noguera NI, Breccia M, Divona M 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: 2185–2189.

164. Shen Y, Shen ZX, Yan H et al. Studies on the clinical efficacy and pharmacokinetics of low-dose arsenic trioxide in the treatment of relapsed acute promyelocytic leukemia: A comparison with conventional dosage. Leukemia 2001; 15: 735–741.

165. Tallman MS, Nabhan C, Feusner JH et al. Acute promyelocytic leukemia: evolving therapeutic strategies. Blood 2002; 99: 759–767.

166. Sanz MA, Tallman MS, Lo-Coco F. Tricks of the trade for the appropriate management of newly diagnosed acute promyelocytic leukemia. Blood 2005; 105: 3019–3025.