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AML1-ETO driven acute leukemia: insights into pathogenesis and potential therapeutic approaches

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Abstract

The AML1-ETO fusion transcription factor is generated by the t(8;21) translocation, which is present in approximately 4%–12% of adult and 12%–30% of pediatric acute myeloid leukemia (AML) patients. Both human and mouse models of AML have demonstrated that AML1-ETO is insufficient for leukemogenesis in the absence of secondary events. In this review, we discuss the pathogenetic insights that have been gained from identifying the various events that can cooperate with AML1-ETO to induce AML in vivo. We also discuss potential therapeutic strategies for t(8;21) positive AML that involve targeting the fusion protein itself, the proteins that bind to it, or the genes that it regulates. Recently published studies suggest that a targeted therapy for t(8;21) positive AML is feasible and may be coming sometime soon.

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References

  1. Rowley JD. Identificaton of a translocation with quinacrine fluorescence in a patient with acute leukemia. Ann Genet 1973; 16(2): 109–112

    PubMed  CAS  Google Scholar 

  2. Müller AMS, Duque J, Shizuru JA, Lübbert M. Complementing mutations in core binding factor leukemias: from mouse models to clinical applications. Oncogene 2008; 27(44): 5759–5773

    Article  PubMed  CAS  Google Scholar 

  3. Yamasaki H, Era T, Asou N, Sanada I, Matutes E, Yamaguchi K, Takatsuki K. High degree of myeloid differentiation and granulocytosis is associated with t(8;21) smoldering leukemia. Leukemia 1995; 9(7): 1147–1153

    PubMed  CAS  Google Scholar 

  4. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med 1985; 103(4): 620–625

    PubMed  CAS  Google Scholar 

  5. Gao J, Erickson P, Gardiner K, Le Beau MM, Diaz MO, Patterson D, Rowley JD, Drabkin HA. Isolation of a yeast artificial chromosome spanning the 8;21 translocation breakpoint t(8;21) (q22;q22.3) in acute myelogenous leukemia. Proc Natl Acad Sci USA 1991; 88(11): 4882–4886

    Article  PubMed  CAS  Google Scholar 

  6. Miyoshi H, Shimizu K, Kozu T, Maseki N, Kaneko Y, Ohki M. t (8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1. Proc Natl Acad Sci USA 1991; 88(23): 10431–10434

    Article  PubMed  CAS  Google Scholar 

  7. Erickson P, Gao J, Chang KS, Look T, Whisenant E, Raimondi S, Lasher R, Trujillo J, Rowley J, Drabkin H. Identification of breakpoints in t(8;21) acute myelogenous leukemia and isolation of a fusion transcript, AML1/ETO, with similarity to Drosophila segmentation gene, runt. Blood 1992; 80(7): 1825–1831

    PubMed  CAS  Google Scholar 

  8. Erickson PF, Robinson M, Owens G, Drabkin HA. The ETO portion of acute myeloid leukemia t(8;21) fusion transcript encodes a highly evolutionarily conserved, putative transcription factor. Cancer Res 1994; 54(7): 1782–1786

    PubMed  CAS  Google Scholar 

  9. Nisson PE, Watkins PC, Sacchi N. Transcriptionally active chimeric gene derived from the fusion of the AML1 gene and a novel gene on chromosome 8 in t(8;21) leukemic cells. Cancer Genet Cytogenet 1992; 63(2): 81–88

    Article  PubMed  CAS  Google Scholar 

  10. Shimizu K, Miyoshi H, Kozu T, Nagata J, Enomoto K, Maseki N, Kaneko Y, Ohki M. Consistent disruption of the AML1 gene occurs within a single intron in the t(8;21) chromosomal translocation. Cancer Res 1992; 52(24): 6945–6948

    PubMed  CAS  Google Scholar 

  11. Buchholz F, Refaeli Y, Trumpp A, Bishop JM. Inducible chromosomal translocation of AML1 and ETO genes through Cre/loxP-mediated recombination in the mouse. EMBO Rep 2000; 1(2): 133–139

    Article  PubMed  CAS  Google Scholar 

  12. Rhoades KL, Hetherington CJ, Harakawa N, Yergeau DA, Zhou L, Liu LQ, Little MT, Tenen DG, Zhang DE. Analysis of the role of AML1-ETO in leukemogenesis, using an inducible transgenic mouse model. Blood 2000; 96(6): 2108–2115

    PubMed  CAS  Google Scholar 

  13. Higuchi M, O’Brien D, Kumaravelu P, Lenny N, Yeoh EJ, Downing JR. Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia. Cancer Cell 2002; 1(1): 63–74

    Article  PubMed  CAS  Google Scholar 

  14. Yuan Y, Zhou L, Miyamoto T, Iwasaki H, Harakawa N, Hetherington CJ, Burel SA, Lagasse E, Weissman IL, Akashi K, Zhang DE. AML1-ETO expression is directly involved in the development of acute myeloid leukemia in the presence of additional mutations. Proc Natl Acad Sci USA 2001; 98(18): 10398–10403

    Article  PubMed  CAS  Google Scholar 

  15. Fenske TS, Pengue G, Mathews V, Hanson PT, Hamm SE, Riaz N, Graubert TA. Stem cell expression of the AML1/ETO fusion protein induces a myeloproliferative disorder in mice. Proc Natl Acad Sci USA 2004; 101(42): 15184–15189

    Article  PubMed  CAS  Google Scholar 

  16. Okuda T, van Deursen J, Hiebert SW, Grosveld G, Downing JR. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 1996; 84(2): 321–330

    Article  PubMed  CAS  Google Scholar 

  17. Wang Q, Stacy T, Binder M, Marin-Padilla M, Sharpe AH, Speck NA. Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. Proc Natl Acad Sci USA 1996; 93(8): 3444–3449

    Article  PubMed  CAS  Google Scholar 

  18. Calabi F, Pannell R, Pavloska G. Gene targeting reveals a crucial role for MTG8 in the gut. Mol Cell Biol 2001; 21(16): 5658–5666

    Article  PubMed  CAS  Google Scholar 

  19. Wang J, Hoshino T, Redner RL, Kajigaya S, Liu JM. ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex. Proc Natl Acad Sci USA 1998; 95(18): 10860–10865

    Article  PubMed  CAS  Google Scholar 

  20. Lutterbach B, Westendorf JJ, Linggi B, Patten A, Moniwa M, Davie JR, Huynh KD, Bardwell VJ, Lavinsky RM, Rosenfeld MG, Glass C, Seto E, Hiebert SW. ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors. Mol Cell Biol 1998; 18(12): 7176–7184

    PubMed  CAS  Google Scholar 

  21. Gelmetti V, Zhang J, Fanelli M, Minucci S, Pelicci PG, Lazar MA. Aberrant recruitment of the nuclear receptor corepressor-histone deacetylase complex by the acute myeloid leukemia fusion partner ETO. Mol Cell Biol 1998; 18(12): 7185–7191

    PubMed  CAS  Google Scholar 

  22. Frank R, Zhang J, Uchida H, Meyers S, Hiebert SW, Nimer SD. The AML1/ETO fusion protein blocks transactivation of the GMCSF promoter by AML1B. Oncogene 1995; 11(12): 2667–2674

    PubMed  CAS  Google Scholar 

  23. Meyers S, Lenny N, Hiebert SW. The t(8;21) fusion protein interferes with AML-1B-dependent transcriptional activation. Mol Cell Biol 1995; 15(4): 1974–1982

    PubMed  CAS  Google Scholar 

  24. Yergeau DA, Hetherington CJ, Wang Q, Zhang P, Sharpe AH, Binder M, Marín-Padilla M, Tenen DG, Speck NA, Zhang DE. Embryonic lethality and impairment of haematopoiesis in mice heterozygous for an AML1-ETO fusion gene. Nat Genet 1997; 15(3): 303–306

    Article  PubMed  CAS  Google Scholar 

  25. Okuda T, Cai Z, Yang S, Lenny N, Lyu CJ, van Deursen JM, Harada H, Downing JR. Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of normal definitive hematopoiesis and directly generates dysplastic hematopoietic progenitors. Blood 1998; 91(9): 3134–3143

    PubMed  CAS  Google Scholar 

  26. Kühn R, Schwenk F, Aguet M, Rajewsky K. Inducible gene targeting in mice. Science 1995; 269(5229): 1427–1429

    Article  PubMed  Google Scholar 

  27. Frei JV, Lawley PD. Thymomas induced by simple alkylating agents in C57BL/Cbi mice: kinetics of the dose response. J Natl Cancer Inst 1980; 64(4): 845–856

    PubMed  CAS  Google Scholar 

  28. Wiemels JL, Xiao Z, Buffler PA, Maia AT, Ma X, Dicks BM, Smith MT, Zhang L, Feusner J, Wiencke J, Pritchard-Jones K, Kempski H, Greaves M. In utero origin of t(8;21) AML1-ETO translocations in childhood acute myeloid leukemia. Blood 2002; 99(10): 3801–3805

    Article  PubMed  CAS  Google Scholar 

  29. Ley TJ, Mardis ER, Ding L, Fulton B, McLellan MD, Chen K, Dooling D, Dunford-Shore BH, McGrath S, Hickenbotham M, Cook L, Abbott R, Larson DE, Koboldt DC, Pohl C, Smith S, Hawkins A, Abbott S, Locke D, Hillier LW, Miner T, Fulton L, Magrini V, Wylie T, Glasscock J, Conyers J, Sander N, Shi X, Osborne JR, Minx P, Gordon D, Chinwalla A, Zhao Y, Ries RE, Payton JE, Westervelt P, Tomasson MH, Watson M, Baty J, Ivanovich J, Heath S, Shannon WD, Nagarajan R, Walter MJ, Link DC, Graubert TA, DiPersio JF, Wilson RK. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature 2008; 456(7218): 66–72

    Article  PubMed  CAS  Google Scholar 

  30. Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, Koboldt DC, Fulton RS, Delehaunty KD, McGrath SD, Fulton LA, Locke DP, Magrini VJ, Abbott RM, Vickery TL, Reed JS, Robinson JS, Wylie T, Smith SM, Carmichael L, Eldred JM, Harris CC, Walker J, Peck JB, Du F, Dukes AF, Sanderson GE, Brummett AM, Clark E, McMichael JF, Meyer RJ, Schindler JK, Pohl CS, Wallis JW, Shi X, Lin L, Schmidt H, Tang Y, Haipek C, Wiechert ME, Ivy JV, Kalicki J, Elliott G, Ries RE, Payton JE, Westervelt P, Tomasson MH, Watson MA, Baty J, Heath S, Shannon WD, Nagarajan R, Link DC, Walter MJ, Graubert TA, DiPersio JF, Wilson RK, Ley TJ. Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med 2009; 361(11): 1058–1066

    Article  PubMed  CAS  Google Scholar 

  31. Peterson LF, Boyapati A, Ahn EY, Biggs JR, Okumura AJ, Lo MC, Yan M, Zhang DE. Acute myeloid leukemia with the 8q22;21q22 translocation: secondary mutational events and alternative t(8;21) transcripts. Blood 2007; 110(3): 799–805

    Article  PubMed  CAS  Google Scholar 

  32. de Guzman CG, Warren AJ, Zhang Z, Gartland L, Erickson P, Drabkin H, Hiebert SW, Klug CA. Hematopoietic stem cell expansion and distinct myeloid developmental abnormalities in a murine model of the AML1-ETO translocation. Mol Cell Biol 2002; 22(15): 5506–5517

    Article  PubMed  CAS  Google Scholar 

  33. Grisolano JL, O’Neal J, Cain J, Tomasson MH. An activated receptor tyrosine kinase, TEL/PDGFbetaR, cooperates with AML1/ETO to induce acute myeloid leukemia in mice. Proc Natl Acad Sci USA 2003; 100(16): 9506–9511

    Article  PubMed  CAS  Google Scholar 

  34. Schessl C, Rawat VP, Cusan M, Deshpande A, Kohl TM, Rosten PM, Spiekermann K, Humphries RK, Schnittger S, Kern W, Hiddemann W, Quintanilla-Martinez L, Bohlander SK, Feuring-Buske M, Buske C. The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice. J Clin Invest 2005; 115(8): 2159–2168

    Article  PubMed  CAS  Google Scholar 

  35. Wang YY, Zhao LJ, Wu CF, Liu P, Shi L, Liang Y, Xiong SM, Mi JQ, Chen Z, Ren R, Chen SJ. C-KIT mutation cooperates with fulllength AML1-ETO to induce acute myeloid leukemia in mice. Proc Natl Acad Sci USA 2011; 108(6): 2450–2455

    Article  PubMed  CAS  Google Scholar 

  36. Gilliland DG, Griffin JD. Role of FLT3 in leukemia. Curr Opin Hematol 2002; 9(4): 274–281

    Article  PubMed  Google Scholar 

  37. Dash A, Gilliland DG. Molecular genetics of acute myeloid leukaemia. Best Pract Res Clin Haematol 2001; 14(1): 49–64

    Article  PubMed  CAS  Google Scholar 

  38. Gilliland DG. Molecular genetics of human leukemias: new insights into therapy. Semin Hematol 2002; 39(4 Suppl 3): 6–11

    Article  PubMed  CAS  Google Scholar 

  39. Tefferi A, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, Patnaik MM, Hanson CA, Pardanani A, Gilliland DG, Levine RL. Detection of mutant TET2 in myeloid malignancies other than myeloproliferative neoplasms: CMML, MDS, MDS/MPN and AML. Leukemia 2009; 23(7): 1343–1345

    Article  PubMed  CAS  Google Scholar 

  40. Ley TJ, Ding L, Walter MJ, McLellan MD, Lamprecht T, Larson DE, Kandoth C, Payton JE, Baty J, Welch J, Harris CC, Lichti CF, Townsend RR, Fulton RS, Dooling DJ, Koboldt DC, Schmidt H, Zhang Q, Osborne JR, Lin L, O’Laughlin M, McMichael JF, Delehaunty KD, McGrath SD, Fulton LA, Magrini VJ, Vickery TL, Hundal J, Cook LL, Conyers JJ, Swift GW, Reed JP, Alldredge PA, Wylie T, Walker J, Kalicki J, Watson MA, Heath S, Shannon WD, Varghese N, Nagarajan R, Westervelt P, Tomasson MH, Link DC, Graubert TA, DiPersio JF, Mardis ER, Wilson RK. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010; 363(25): 2424–2433

    Article  PubMed  CAS  Google Scholar 

  41. Carbuccia N, Trouplin V, Gelsi-Boyer V, Murati A, Rocquain J, Adélaïde J, Olschwang S, Xerri L, Vey N, Chaffanet M, Birnbaum D, Mozziconacci MJ. Mutual exclusion of ASXL1 and NPM1 mutations in a series of acute myeloid leukemias. Leukemia 2010; 24(2): 469–473

    Article  PubMed  CAS  Google Scholar 

  42. Boultwood J, Perry J, Pellagatti A, Fernandez-Mercado M, Fernandez-Santamaria C, Calasanz MJ, Larrayoz MJ, Garcia-Delgado M, Giagounidis A, Malcovati L, Della Porta MG, Jädersten M, Killick S, Hellström-Lindberg E, Cazzola M, Wainscoat JS. Frequent mutation of the polycomb-associated gene ASXL1 in the myelodysplastic syndromes and in acute myeloid leukemia. Leukemia 2010; 24(5): 1062–1065

    Article  PubMed  CAS  Google Scholar 

  43. Menssen HD, Renkl HJ, Rodeck U, Maurer J, Notter M, Schwartz S, Reinhardt R, Thiel E. Presence of Wilms’ tumor gene (wt1) transcripts and the WT1 nuclear protein in the majority of human acute leukemias. Leukemia 1995; 9(6): 1060–1067

    PubMed  CAS  Google Scholar 

  44. Tsuboi A, Oka Y, Ogawa H, Elisseeva OA, Tamaki H, Oji Y, Kim EH, Soma T, Tatekawa T, Kawakami M, Kishimoto T, Sugiyama H. Constitutive expression of theWilms’ tumor gene WT1 inhibits the differentiation of myeloid progenitor cells but promotes their proliferation in response to granulocyte-colony stimulating factor (G-CSF). Leuk Res 1999; 23(5): 499–505

    Article  PubMed  CAS  Google Scholar 

  45. Nishida S, Hosen N, Shirakata T, Kanato K, Yanagihara M, Nakatsuka S, Hoshida Y, Nakazawa T, Harada Y, Tatsumi N, Tsuboi A, Kawakami M, Oka Y, Oji Y, Aozasa K, Kawase I, Sugiyama H. AML1-ETO rapidly induces acute myeloblastic leukemia in cooperation with the Wilms tumor gene, WT1. Blood 2006; 107(8): 3303–3312

    Article  PubMed  CAS  Google Scholar 

  46. Schwieger M, Löhler J, Friel J, Scheller M, Horak I, Stocking C. AML1-ETO inhibits maturation of multiple lymphohematopoietic lineages and induces myeloblast transformation in synergy with ICSBP deficiency. J Exp Med 2002; 196(9): 1227–1240

    Article  PubMed  CAS  Google Scholar 

  47. Tallman MS, Hakimian D, Shaw JM, Lissner GS, Russell EJ, Variakojis D. Granulocytic sarcoma is associated with the 8;21 translocation in acute myeloid leukemia. J Clin Oncol 1993; 11(4): 690–697

    PubMed  CAS  Google Scholar 

  48. Peterson LF, Yan M, Zhang DE. The p21Waf1 pathway is involved in blocking leukemogenesis by the t(8;21) fusion protein AML1-ETO. Blood 2007; 109(10): 4392–4398

    Article  PubMed  CAS  Google Scholar 

  49. Shiohara M, Koike K, Komiyama A, Koeffler HP. p21WAF1 mutations and human malignancies. Leuk Lymphoma 1997; 26(1–2): 35–41

    PubMed  CAS  Google Scholar 

  50. Hayette S, Thomas X, Bertrand Y, Tigaud I, Callanan M, Thiebaut A, Charrin C, Archimbaud E, Magaud JP, Rimokh R. Molecular analysis of cyclin-dependent kinase inhibitors in human leukemias. Leukemia 1997; 11(10): 1696–1699

    Article  PubMed  CAS  Google Scholar 

  51. Chim CS, Wong AS, Kwong YL. Epigenetic inactivation of the CIP/KIP cell-cycle control pathway in acute leukemias. Am J Hematol 2005; 80(4): 282–287

    Article  PubMed  CAS  Google Scholar 

  52. Brakensiek K, Länger F, Kreipe H, Lehmann U. Absence of p21 (CIP 1), p27(KIP 1) and p 57(KIP 2) methylation in MDS and AML. Leuk Res 2005; 29(11): 1357–1360

    Article  PubMed  CAS  Google Scholar 

  53. Berg T, Fliegauf M, Burger J, Staege MS, Liu S, Martinez N, Heidenreich O, Burdach S, Haferlach T, Werner MH, Lübbert M. Transcriptional upregulation of p21/WAF/Cip1 in myeloid leukemic blasts expressing AML1-ETO. Haematologica 2008; 93(11): 1728–1733

    Article  PubMed  CAS  Google Scholar 

  54. Waga S, Hannon GJ, Beach D, Stillman B. The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature 1994; 369(6481): 574–578

    Article  PubMed  CAS  Google Scholar 

  55. Li R, Waga S, Hannon GJ, Beach D, Stillman B. Differential effects by the p21 CDK inhibitor on PCNA-dependent DNA replication and repair. Nature 1994; 371(6497): 534–537

    Article  PubMed  CAS  Google Scholar 

  56. Chuang LS, Ian HI, Koh TW, Ng HH, Xu G, Li BF. Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1. Science 1997; 277(5334): 1996–2000

    Article  PubMed  CAS  Google Scholar 

  57. Yan M, Burel SA, Peterson LF, Kanbe E, Iwasaki H, Boyapati A, Hines R, Akashi K, Zhang DE. Deletion of an AML1-ETO Cterminal NcoR/SMRT-interacting region strongly induces leukemia development. Proc Natl Acad Sci USA 2004; 101(49): 17186–17191

    Article  PubMed  CAS  Google Scholar 

  58. Wolford JK, Prochazka M. Structure and expression of the human MTG8/ETO gene. Gene 1998; 212(1): 103–109

    Article  PubMed  CAS  Google Scholar 

  59. Yan M, Kanbe E, Peterson LF, Boyapati A, Miao Y, Wang Y, Chen IM, Chen Z, Rowley JD, Willman CL, Zhang DE. A previously unidentified alternatively spliced isoform of t(8;21) transcript promotes leukemogenesis. Nat Med 2006; 12(8): 945–949

    Article  PubMed  CAS  Google Scholar 

  60. Jiao B, Wu CF, Liang Y, Chen HM, Xiong SM, Chen B, Shi JY, Wang YY, Wang JH, Chen Y, Li JM, Gu LJ, Tang JY, Shen ZX, Gu BW, Zhao WL, Chen Z, Chen SJ. AML1-ETO9a is correlated with C-KIT overexpression/mutations and indicates poor disease outcome in t(8;21) acute myeloid leukemia-M2. Leukemia 2009; 23(9): 1598–1604

    Article  PubMed  CAS  Google Scholar 

  61. Fey MF, Greil R, Jost LM; ESMO Guidelines Task Force. ESMO Minimum Clinical Recommendations for the diagnosis, treatment and follow-up of acute myeloblastic leukemia (AML) in adult patients. Ann Oncol 2005; 16(Suppl 1): i48–i49

    Article  PubMed  Google Scholar 

  62. Kolitz JE. Current therapeutic strategies for acute myeloid leukaemia. Br J Haematol 2006; 134(6): 555–572

    Article  PubMed  CAS  Google Scholar 

  63. Byrd JC, Mrózek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC, Pettenati MJ, Patil SR, Rao KW, Watson MS, Koduru PR, Moore JO, Stone RM, Mayer RJ, Feldman EJ, Davey FR, Schiffer CA, Larson RA, Bloomfield CD; Cancer and Leukemia Group B (CALGB 8461). Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002; 100(13): 4325–4336

    Article  PubMed  CAS  Google Scholar 

  64. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116(2): 281–297

    Article  PubMed  CAS  Google Scholar 

  65. Ambros V. The functions of animal microRNAs. Nature 2004; 431(7006): 350–355

    Article  PubMed  CAS  Google Scholar 

  66. Zhang B, Wang Q, Pan X. MicroRNAs and their regulatory roles in animals and plants. J Cell Physiol 2007; 210(2): 279–289

    Article  PubMed  CAS  Google Scholar 

  67. Havelange V, Garzon R. MicroRNAs: emerging key regulators of hematopoiesis. Am J Hematol 2010; 85(12): 935–942

    Article  PubMed  CAS  Google Scholar 

  68. Fazi F, Racanicchi S, Zardo G, Starnes LM, Mancini M, Travaglini L, Diverio D, Ammatuna E, Cimino G, Lo-Coco F, Grignani F, Nervi C. Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein. Cancer Cell 2007; 12(5): 457–466

    Article  PubMed  CAS  Google Scholar 

  69. Brioschi M, Fischer J, Cairoli R, Rossetti S, Pezzetti L, Nichelatti M, Turrini M, Corlazzoli F, Scarpati B, Morra E, Sacchi N, Beghini A. Down-regulation of microRNAs 222/221 in acute myelogenous leukemia with deranged core-binding factor subunits. Neoplasia 2010; 12(11): 866–876

    PubMed  CAS  Google Scholar 

  70. Fazi F, Rosa A, Fatica A, Gelmetti V, De Marchis ML, Nervi C, Bozzoni I. A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis. Cell 2005; 123(5): 819–831

    Article  PubMed  CAS  Google Scholar 

  71. Felli N, Fontana L, Pelosi E, Botta R, Bonci D, Facchiano F, Liuzzi F, Lulli V, Morsilli O, Santoro S, Valtieri M, Calin GA, Liu CG, Sorrentino A, Croce CM, Peschle C. MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation. Proc Natl Acad Sci USA 2005; 102(50): 18081–18086

    Article  PubMed  CAS  Google Scholar 

  72. Zaidi SK, Dowdy CR, van Wijnen AJ, Lian JB, Raza A, Stein JL, Croce CM, Stein GS. Altered Runx1 subnuclear targeting enhances myeloid cell proliferation and blocks differentiation by activating a miR-24/MKP-7/MAPK network. Cancer Res 2009; 69(21): 8249–8255

    Article  PubMed  CAS  Google Scholar 

  73. Tanoue T, Yamamoto T, Maeda R, Nishida E. A novel MAPK phosphatase MKP-7 acts preferentially on JNK/SAPK and p38 alpha and beta MAPKs. J Biol Chem 2001; 276(28): 26629–26639

    Article  PubMed  CAS  Google Scholar 

  74. Li Z, Lu J, Sun M, Mi S, Zhang H, Luo RT, Chen P, Wang Y, Yan M, Qian Z, Neilly MB, Jin J, Zhang Y, Bohlander SK, Zhang DE, Larson RA, Le Beau MM, Thirman MJ, Golub TR, Rowley JD, Chen J. Distinct microRNA expression profiles in acute myeloid leukemia with common translocations. Proc Natl Acad Sci USA 2008; 105(40): 15535–15540

    Article  PubMed  CAS  Google Scholar 

  75. Valk PJ, Verhaak RG, Beijen MA, Erpelinck CA, Barjesteh van Waalwijk van Doorn-Khosrovani S, Boer JM, Beverloo HB, Moorhouse MJ, van der Spek PJ, Löwenberg B, Delwel R. Prognostically useful gene-expression profiles in acute myeloid leukemia. N Engl J Med 2004; 350(16): 1617–1628

    Article  PubMed  CAS  Google Scholar 

  76. Bullinger L, Döhner K, Bair E, Fröhling S, Schlenk RF, Tibshirani R, Döhner H, Pollack JR. Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. N Engl J Med 2004; 350(16): 1605–1616

    Article  PubMed  CAS  Google Scholar 

  77. Müller-Tidow C, Steffen B, Cauvet T, Tickenbrock L, Ji P, Diederichs S, Sargin B, Köhler G, Stelljes M, Puccetti E, Ruthardt M, deVos S, Hiebert SW, Koeffler HP, Berdel WE, Serve H. Translocation products in acute myeloid leukemia activate the Wnt signaling pathway in hematopoietic cells. Mol Cell Biol 2004; 24(7): 2890–2904

    Article  PubMed  CAS  Google Scholar 

  78. Steffen B, Knop M, Bergholz U, Vakhrusheva O, Rode M, Köhler G, Henrichs MP, Bulk E, Hehn S, Stehling M, Dugas M, Bäumer N, Tschanter P, Brandts C, Koschmieder S, Berdel WE, Serve H, Stocking C, Müller-Tidow C. AML1/ETO induces self-renewal in hematopoietic progenitor cells via the Groucho-related aminoterminal AES protein. Blood 2011; 117(16): 4328–4337

    Article  PubMed  CAS  Google Scholar 

  79. Balkhi MY, Trivedi AK, Geletu M, Christopeit M, Bohlander SK, Behre HM, Behre G. Proteomics of acute myeloid leukaemia: cytogenetic risk groups differ specifically in their proteome, interactome and post-translational protein modifications. Oncogene 2006; 25(53): 7041–7058

    Article  PubMed  CAS  Google Scholar 

  80. Balkhi MY, Christopeit M, Chen Y, Geletu M, Behre G. AML1/ ETO-induced survivin expression inhibits transcriptional regulation of myeloid differentiation. Exp Hematol 2008; 36(11): 1449–1460.e1

    Article  PubMed  CAS  Google Scholar 

  81. Rohayem J, Diestelkoetter P, Weigle B, Oehmichen A, Schmitz M, Mehlhorn J, Conrad K, Rieber EP. Antibody response to the tumor-associated inhibitor of apoptosis protein survivin in cancer patients. Cancer Res 2000; 60(7): 1815–1817

    PubMed  CAS  Google Scholar 

  82. Hirohashi Y, Torigoe T, Maeda A, Nabeta Y, Kamiguchi K, Sato T, Yoda J, Ikeda H, Hirata K, Yamanaka N, Sato N. An HLA-A24-restricted cytotoxic T lymphocyte epitope of a tumor-associated protein, survivin. Clin Cancer Res 2002; 8(6): 1731–1739

    PubMed  CAS  Google Scholar 

  83. Bacher U, Haferlach T, Schoch C, Kern W, Schnittger S. Implications of NRAS mutations in AML: a study of 2502 patients. Blood 2006; 107(10): 3847–3853

    Article  PubMed  CAS  Google Scholar 

  84. Kuchenbauer F, Schnittger S, Look T, Gilliland G, Tenen D, Haferlach T, Hiddemann W, Buske C, Schoch C. Identification of additional cytogenetic and molecular genetic abnormalities in acute myeloid leukaemia with t(8;21)/AML1-ETO. Br J Haematol 2006; 134(6): 616–619

    Article  PubMed  CAS  Google Scholar 

  85. Chou FS, Wunderlich M, Griesinger A, Mulloy JC. N-Ras(G12D) induces features of stepwise transformation in preleukemic human umbilical cord blood cultures expressing the AML1-ETO fusion gene. Blood 2011; 117(7): 2237–2240

    Article  PubMed  CAS  Google Scholar 

  86. Klampfer L, Zhang J, Zelenetz AO, Uchida H, Nimer SD. The AML1/ETO fusion protein activates transcription of BCL-2. Proc Natl Acad Sci USA 1996; 93(24): 14059–14064

    Article  PubMed  CAS  Google Scholar 

  87. Chou FS, Griesinger A, Wunderlich M, Lin S, Link KA, Shrestha M, Goyama S, Mizukawa B, Shen S, Marcucci G, Mulloy JC. The THPO/MPL/Bcl-xL pathway is essential for survival and selfrenewal in human pre-leukemia induced by AML1-ETO. Blood 2012 Feb 14. [Epub ahead of print] doi: 10.1182/blood-2012-01-403212

  88. Osman D, Gobert V, Ponthan F, Heidenreich O, Haenlin M, Waltzer L. A Drosophila model identifies calpains as modulators of the human leukemogenic fusion protein AML1-ETO. Proc Natl Acad Sci USA 2009; 106(29): 12043–12048

    Article  PubMed  CAS  Google Scholar 

  89. Corsello SM, Roti G, Ross KN, Chow KT, Galinsky I, DeAngelo DJ, Stone RM, Kung AL, Golub TR, Stegmaier K. Identification of AML1-ETO modulators by chemical genomics. Blood 2009; 113(24): 6193–6205

    Article  PubMed  CAS  Google Scholar 

  90. Shimohakamada Y, Shinohara K, Fukuda N. Remission of acute myeloblastic leukemia after severe pneumonia treated with highdose methylprednisolone. Int J Hematol 2001; 74(2): 173–177

    Article  PubMed  CAS  Google Scholar 

  91. Yeh JR, Munson KM, Elagib KE, Goldfarb AN, Sweetser DA, Peterson RT. Discovering chemical modifiers of oncogeneregulated hematopoietic differentiation. Nat Chem Biol 2009; 5(4): 236–243

    Article  PubMed  CAS  Google Scholar 

  92. Zhou GB, Kang H, Wang L, Gao L, Liu P, Xie J, Zhang FX, Weng XQ, Shen ZX, Chen J, Gu LJ, Yan M, Zhang DE, Chen SJ, Wang ZY, Chen Z. Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8;21) leukemia in vitro and in vivo. Blood 2007; 109(8): 3441–3450

    Article  PubMed  CAS  Google Scholar 

  93. Wang L, Zhao WL, Yan JS, Liu P, Sun HP, Zhou GB, Weng ZY, Wu WL, Weng XQ, Sun XJ, Chen Z, Sun HD, Chen SJ. Eriocalyxin B induces apoptosis of t(8;21) leukemia cells through NF-kappaB and MAPK signaling pathways and triggers degradation of AML1-ETO oncoprotein in a caspase-3-dependent manner. Cell Death Differ 2007; 14(2): 306–317

    Article  PubMed  CAS  Google Scholar 

  94. Zhou GS, Hu Z, Fang HT, Zhang FX, Pan XF, Chen XQ, Hu AM, Xu L, Zhou GB. Biologic activity of triptolide in t(8;21) acute myeloid leukemia cells. Leuk Res 2011; 35(2): 214–218

    Article  PubMed  CAS  Google Scholar 

  95. Wang YY, Zhou GB, Yin T, Chen B, Shi JY, Liang WX, Jin XL, You JH, Yang G, Shen ZX, Chen J, Xiong SM, Chen GQ, Xu F, Liu YW, Chen Z, Chen SJ. AML1-ETO and C-KIT mutation/ overexpression in t(8;21) leukemia: implication in stepwise leukemogenesis and response to Gleevec. Proc Natl Acad Sci USA 2005; 102(4): 1104–1109

    Article  PubMed  CAS  Google Scholar 

  96. Fang HT, Zhang B, Pan XF, Gao L, Zhen T, Zhao HX, Ma L, Xie J, Liu Z, Yu XJ, Cheng X, Feng TT, Zhang FX, Yang Y, Hu ZG, Sheng GQ, Chen YL, Chen SJ, Chen Z, Zhou GB. Bortezomib interferes with C-KIT processing and transforms the t(8;21)-generated fusion proteins into tumor-suppressing fragments in leukemia cells. Proc Natl Acad Sci USA 2012; 109(7): 2521–2526

    Article  PubMed  CAS  Google Scholar 

  97. Liu S, Liu Z, Xie Z, Pang J, Yu J, Lehmann E, Huynh L, Vukosavljevic T, Takeki M, Klisovic RB, Baiocchi RA, Blum W, Porcu P, Garzon R, Byrd JC, Perrotti D, Caligiuri MA, Chan KK, Wu LC, Marcucci G. Bortezomib induces DNA hypomethylation and silenced gene transcription by interfering with Sp1/NF-κBdependent DNA methyltransferase activity in acute myeloid leukemia. Blood 2008; 111(4): 2364–2373

    Article  PubMed  CAS  Google Scholar 

  98. Maiques-Diaz A, Chou FS, Wunderlich M, Gómez-López G, Jacinto FV, Rodriguez-Perales S, Larrayoz MJ, Calasanz MJ, Mulloy JC, Cigudosa JC, Alvarez S. Chromatin modifications induced by the AML1-ETO fusion protein reversibly silence its genomic targets through AML1 and Sp1 binding motifs. Leukemia 2012 Jan 13. [Epub ahead of print] doi: 10.1038/leu.2011.376

  99. Shankar S, Srivastava RK. Histone deacetylase inhibitors: mechanisms and clinical significance in cancer: HDAC inhibitorinduced apoptosis. Adv Exp Med Biol 2008; 615: 261–298

    Article  PubMed  CAS  Google Scholar 

  100. Lutterbach B, Westendorf JJ, Linggi B, Patten A, Moniwa M, Davie JR, Huynh KD, Bardwell VJ, Lavinsky RM, Rosenfeld MG, Glass C, Seto E, Hiebert SW. ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors. Mol Cell Biol 1998; 18(12): 7176–7184

    PubMed  CAS  Google Scholar 

  101. Klisovic MI, Maghraby EA, Parthun MR, Guimond M, Sklenar AR, Whitman SP, Chan KK, Murphy T, Anon J, Archer KJ, Rush LJ, Plass C, Grever MR, Byrd JC, Marcucci G. Depsipeptide (FR 901228) promotes histone acetylation, gene transcription, apoptosis and its activity is enhanced by DNA methyltransferase inhibitors in AML1/ETO-positive leukemic cells. Leukemia 2003; 17(2): 350–358

    Article  PubMed  CAS  Google Scholar 

  102. Yang G, Thompson MA, Brandt SJ, Hiebert SW. Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein. Oncogene 2007; 26(1): 91–101

    Article  PubMed  CAS  Google Scholar 

  103. Fuino L, Bali P, Wittmann S, Donapaty S, Guo F, Yamaguchi H, Wang HG, Atadja P, Bhalla K. Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. Mol Cancer Ther 2003; 2(10): 971–984

    PubMed  CAS  Google Scholar 

  104. Yu X, Guo ZS, Marcu MG, Neckers L, Nguyen DM, Chen GA, Schrump DS. Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228. J Natl Cancer Inst 2002; 94(7): 504–513

    Article  PubMed  CAS  Google Scholar 

  105. Kitabayashi I, Yokoyama A, Shimizu K, Ohki M. Interaction and functional cooperation of the leukemia-associated factors AML1 and p300 in myeloid cell differentiation. EMBO J 1998; 17(11): 2994–3004

    Article  PubMed  CAS  Google Scholar 

  106. Yamaguchi Y, Kurokawa M, Imai Y, Izutsu K, Asai T, Ichikawa M, Yamamoto G, Nitta E, Yamagata T, Sasaki K, Mitani K, Ogawa S, Chiba S, Hirai H. AML1 is functionally regulated through p300-mediated acetylation on specific lysine residues. J Biol Chem 2004; 279(15): 15630–15638

    Article  PubMed  CAS  Google Scholar 

  107. Wang L, Gural A, Sun XJ, Zhao X, Perna F, Huang G, Hatlen MA, Vu L, Liu F, Xu H, Asai T, Xu H, Deblasio T, Menendez S, Voza F, Jiang Y, Cole PA, Zhang J, Melnick A, Roeder RG, Nimer SD. The leukemogenicity of AML1-ETO is dependent on site-specific lysine acetylation. Science 2011; 333(6043): 765–769

    Article  PubMed  CAS  Google Scholar 

  108. Zheng Y, Balasubramanyam K, Cebrat M, Buck D, Guidez F, Zelent A, Alani RM, Cole PA. Synthesis and evaluation of a potent and selective cell-permeable p300 histone acetyltransferase inhibitor. J Am Chem Soc 2005; 127(49): 17182–17183

    Article  PubMed  CAS  Google Scholar 

  109. Bowers EM, Yan G, Mukherjee C, Orry A, Wang L, Holbert MA, Crump NT, Hazzalin CA, Liszczak G, Yuan H, Larocca C, Saldanha SA, Abagyan R, Sun Y, Meyers DJ, Marmorstein R, Mahadevan LC, Alani RM, Cole PA. Virtual ligand screening of the p300/CBP histone acetyltransferase: identification of a selective small molecule inhibitor. Chem Biol 2010; 17(5): 471–482

    Article  PubMed  CAS  Google Scholar 

  110. Wang L, Huang G, Zhao X, Hatlen MA, Vu L, Liu F, Nimer SD. Post-translational modifications of Runx1 regulate its activity in the cell. Blood Cells Mol Dis 2009; 43(1): 30–34

    Article  PubMed  CAS  Google Scholar 

  111. Mulloy JC, Cammenga J, MacKenzie KL, Berguido FJ, Moore MA, Nimer SD. The AML1-ETO fusion protein promotes the expansion of human hematopoietic stem cells. Blood 2002; 99(1): 15–23

    Article  PubMed  CAS  Google Scholar 

  112. Mulloy JC, Cammenga J, Berguido FJ, Wu K, Zhou P, Comenzo RL, Jhanwar S, Moore MA, Nimer SD. Maintaining the selfrenewal and differentiation potential of human CD34+ hematopoietic cells using a single genetic element. Blood 2003; 102(13): 4369–4376

    Article  PubMed  CAS  Google Scholar 

  113. Bäsecke J, Schwieger M, Griesinger F, Schiedlmeier B, Wulf G, Trümper L, Stocking C. AML1/ETO promotes the maintenance of early hematopoietic progenitors in NOD/SCID mice but does not abrogate their lineage specific differentiation. Leuk Lymphoma 2005; 46(2): 265–272

    Article  PubMed  CAS  Google Scholar 

  114. Licht JD. AML1 and the AML1-ETO fusion protein in the pathogenesis of t(8;21) AML. Oncogene 2001; 20(40): 5660–5679

    Article  PubMed  CAS  Google Scholar 

  115. Nimer SD, Moore MA. Effects of the leukemia-associated AML1-ETO protein on hematopoietic stem and progenitor cells. Oncogene 2004; 23(24): 4249–4254

    Article  PubMed  CAS  Google Scholar 

  116. Peterson LF, Zhang DE. The 8;21 translocation in leukemogenesis. Oncogene 2004; 23(24): 4255–4262

    Article  PubMed  CAS  Google Scholar 

  117. Tabe Y, Jin L, Contractor R, Gold D, Ruvolo P, Radke S, Xu Y, Tsutusmi-Ishii Y, Miyake K, Miyake N, Kondo S, Ohsaka A, Nagaoka I, Andreeff M, Konopleva M. Novel role of HDAC inhibitors in AML1/ETO AML cells: activation of apoptosis and phagocytosis through induction of annexin A1. Cell Death Differ 2007; 14(8): 1443–1456

    Article  PubMed  CAS  Google Scholar 

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  1. Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA

    Megan A. Hatlen, Lan Wang & Stephen D. Nimer

  2. Weill Cornell Medical College, New York, NY, 10065, USA

    Megan A. Hatlen & Stephen D. Nimer

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  1. Megan A. Hatlen
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Hatlen, M.A., Wang, L. & Nimer, S.D. AML1-ETO driven acute leukemia: insights into pathogenesis and potential therapeutic approaches. Front. Med. 6, 248–262 (2012). https://doi.org/10.1007/s11684-012-0206-6

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