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

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.

Keywords

AML1-ETO / mouse model / leukemia / t(8;21) / pathway hits / mutation / hematopoiesis / Kasumi-1; CD34⁺

References

[1] Rowley JD. Identificaton of a translocation with quinacrine fluorescence in a patient with acute leukemia. Ann Genet1973; 16(2): 109-112

[2] Müller AMS, Duque J, Shizuru JA, Lübbert M. Complementing mutations in core binding factor leukemias: from mouse models to clinical applications. Oncogene2008; 27(44): 5759-5773

[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. Leukemia1995; 9(7): 1147-1153

[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 Med1985; 103(4): 620-625

[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 USA1991; 88(11): 4882-4886

[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 USA1991; 88(23): 10431-10434

[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. Blood1992; 80(7): 1825-1831

[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 Res1994; 54(7): 1782-1786

[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 Cytogenet1992; 63(2): 81-88

[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 Res1992; 52(24): 6945-6948

[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 Rep2000; 1(2): 133-139

[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. Blood2000; 96(6): 2108-2115

[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 Cell2002; 1(1): 63-74

[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 USA2001; 98(18): 10398-10403

[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 USA2004; 101(42): 15184-15189

[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. Cell1996; 84(2): 321-330

[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 USA1996; 93(8): 3444-3449

[18] Calabi F, Pannell R, Pavloska G. Gene targeting reveals a crucial role for MTG8 in the gut. Mol Cell Biol2001; 21(16): 5658-5666

[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 USA1998; 95(18): 10860-10865

[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 Biol1998; 18(12): 7176-7184

[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 Biol1998; 18(12): 7185-7191

[22] Frank R, Zhang J, Uchida H, Meyers S, Hiebert SW, Nimer SD. The AML1/ETO fusion protein blocks transactivation of the GM-CSF promoter by AML1B. Oncogene1995; 11(12): 2667-2674

[23] Meyers S, Lenny N, Hiebert SW. The t(8;21) fusion protein interferes with AML-1B-dependent transcriptional activation. Mol Cell Biol1995; 15(4): 1974-1982

[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 Genet1997; 15(3): 303-306

[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. Blood1998; 91(9): 3134-3143

[26] Kühn R, Schwenk F, Aguet M, Rajewsky K. Inducible gene targeting in mice. Science1995; 269(5229): 1427-1429

[27] Frei JV, Lawley PD. Thymomas induced by simple alkylating agents in C57BL/Cbi mice: kinetics of the dose response. J Natl Cancer Inst1980; 64(4): 845-856

[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. Blood2002; 99(10): 3801-3805

[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. Nature2008; 456(7218): 66-72

[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 Med2009; 361(11): 1058-1066

[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. Blood2007; 110(3): 799-805

[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 Biol2002; 22(15): 5506-5517

[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 USA2003; 100(16): 9506-9511

[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 Invest2005; 115(8): 2159-2168

[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 full-length AML1-ETO to induce acute myeloid leukemia in mice. Proc Natl Acad Sci USA2011; 108(6): 2450-2455

[36] Gilliland DG, Griffin JD. Role of FLT3 in leukemia. Curr Opin Hematol2002; 9(4): 274-281

[37] Dash A, Gilliland DG. Molecular genetics of acute myeloid leukaemia. Best Pract Res Clin Haematol2001; 14(1): 49-64

[38] Gilliland DG. Molecular genetics of human leukemias: new insights into therapy. Semin Hematol2002; 39(4 Suppl 3): 6-11

[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. Leukemia2009; 23(7): 1343-1345

[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 Med2010; 363(25): 2424-2433

[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. Leukemia2010; 24(2): 469-473

[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. Leukemia2010; 24(5): 1062-1065

[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. Leukemia1995; 9(6): 1060-1067

[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 the Wilms’ tumor gene WT1 inhibits the differentiation of myeloid progenitor cells but promotes their proliferation in response to granulocyte-colony stimulating factor (G-CSF). Leuk Res1999; 23(5): 499-505

[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. Blood2006; 107(8): 3303-3312

[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 Med2002; 196(9): 1227-1240

[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 Oncol1993; 11(4): 690-697

[48] Peterson LF, Yan M, Zhang DE. The p21Waf1 pathway is involved in blocking leukemogenesis by the t(8;21) fusion protein AML1-ETO. Blood2007; 109(10): 4392-4398

[49] Shiohara M, Koike K, Komiyama A, Koeffler HP. p21WAF1 mutations and human malignancies. Leuk Lymphoma1997; 26(1-2): 35-41

[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. Leukemia1997; 11(10): 1696-1699

[51] Chim CS, Wong AS, Kwong YL. Epigenetic inactivation of the CIP/KIP cell-cycle control pathway in acute leukemias. Am J Hematol2005; 80(4): 282-287

[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 Res2005; 29(11): 1357-1360

[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. Haematologica2008; 93(11): 1728-1733

[54] Waga S, Hannon GJ, Beach D, Stillman B. The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature1994; 369(6481): 574-578

[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. Nature1994; 371(6497): 534-537

[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. Science1997; 277(5334): 1996-2000

[57] Yan M, Burel SA, Peterson LF, Kanbe E, Iwasaki H, Boyapati A, Hines R, Akashi K, Zhang DE. Deletion of an AML1-ETO C-terminal NcoR/SMRT-interacting region strongly induces leukemia development. Proc Natl Acad Sci USA2004; 101(49): 17186-17191

[58] Wolford JK, Prochazka M. Structure and expression of the human MTG8/ETO gene. Gene1998; 212(1): 103-109

[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 Med2006; 12(8): 945-949

[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. Leukemia2009; 23(9): 1598-1604

[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 Oncol2005; 16(Suppl 1): i48-i49

[62] Kolitz JE. Current therapeutic strategies for acute myeloid leukaemia. Br J Haematol2006; 134(6): 555-572

[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). Blood2002; 100(13): 4325-4336

[64] Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell2004; 116(2): 281-297

[65] Ambros V. The functions of animal microRNAs. Nature2004; 431(7006): 350-355

[66] Zhang B, Wang Q, Pan X. MicroRNAs and their regulatory roles in animals and plants. J Cell Physiol2007; 210(2): 279-289

[67] Havelange V, Garzon R. MicroRNAs: emerging key regulators of hematopoiesis. Am J Hematol2010; 85(12): 935-942

[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 Cell2007; 12(5): 457-466

[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. Neoplasia2010; 12(11): 866-876

[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. Cell2005; 123(5): 819-831

[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 USA2005; 102(50): 18081-18086

[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 Res2009; 69(21): 8249-8255

[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 Chem2001; 276(28): 26629-26639

[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 USA2008; 105(40): 15535-15540

[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 Med2004; 350(16): 1617-1628

[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 Med2004; 350(16): 1605-1616

[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 Biol2004; 24(7): 2890-2904

[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 amino-terminal AES protein. Blood2011; 117(16): 4328-4337

[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. Oncogene2006; 25(53): 7041-7058

[80] Balkhi MY, Christopeit M, Chen Y, Geletu M, Behre G. AML1/ETO-induced survivin expression inhibits transcriptional regulation of myeloid differentiation. Exp Hematol2008; 36(11): 1449-1460.e1

[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 Res2000; 60(7): 1815-1817

[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 Res2002; 8(6): 1731-1739

[83] Bacher U, Haferlach T, Schoch C, Kern W, Schnittger S. Implications of NRAS mutations in AML: a study of 2502 patients. Blood2006; 107(10): 3847-3853

[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 Haematol2006; 134(6): 616-619

[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. Blood2011; 117(7): 2237-2240

[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 USA1996; 93(24): 14059-14064

[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 self-renewal in human pre-leukemia induced by AML1-ETO. Blood 2012<month>Feb</month><day>14</day>. [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 USA2009; 106(29): 12043-12048

[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. Blood2009; 113(24): 6193-6205

[90] Shimohakamada Y, Shinohara K, Fukuda N. Remission of acute myeloblastic leukemia after severe pneumonia treated with high-dose methylprednisolone. Int J Hematol2001; 74(2): 173-177

[91] Yeh JR, Munson KM, Elagib KE, Goldfarb AN, Sweetser DA, Peterson RT. Discovering chemical modifiers of oncogene-regulated hematopoietic differentiation. Nat Chem Biol2009; 5(4): 236-243

[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. Blood2007; 109(8): 3441-3450

[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 Differ2007; 14(2): 306-317

[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 Res2011; 35(2): 214-218

[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 USA2005; 102(4): 1104-1109

[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 USA2012; 109(7): 2521-2526

[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-κB-dependent DNA methyltransferase activity in acute myeloid leukemia. Blood2008; 111(4): 2364-2373

[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. Leukemia2012<month>Jan</month><day>13</day>. [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 inhibitor-induced apoptosis. Adv Exp Med Biol2008; 615: 261-298

[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 Biol1998; 18(12): 7176-7184

[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. Leukemia2003; 17(2): 350-358

[102] Yang G, Thompson MA, Brandt SJ, Hiebert SW. Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein. Oncogene2007; 26(1): 91-101

[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 Ther2003; 2(10): 971-984

[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 Inst2002; 94(7): 504-513

[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 J1998; 17(11): 2994-3004

[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 Chem2004; 279(15): 15630-15638

[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. Science2011; 333(6043): 765-769

[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 Soc2005; 127(49): 17182-17183

[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 Biol2010; 17(5): 471-482

[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 Dis2009; 43(1): 30-34

[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. Blood2002; 99(1): 15-23

[112] Mulloy JC, Cammenga J, Berguido FJ, Wu K, Zhou P, Comenzo RL, Jhanwar S, Moore MA, Nimer SD. Maintaining the self-renewal and differentiation potential of human CD34⁺ hematopoietic cells using a single genetic element. Blood2003; 102(13): 4369-4376

[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 Lymphoma2005; 46(2): 265-272

[114] Licht JD. AML1 and the AML1-ETO fusion protein in the pathogenesis of t(8;21) AML. Oncogene2001; 20(40): 5660-5679

[115] Nimer SD, Moore MA. Effects of the leukemia-associated AML1-ETO protein on hematopoietic stem and progenitor cells. Oncogene2004; 23(24): 4249-4254

[116] Peterson LF, Zhang DE. The 8;21 translocation in leukemogenesis. Oncogene2004; 23(24): 4255-4262

[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 Differ2007; 14(8): 1443-1456

Acknowledgements

This work is supported by a Leukemia Lymphoma Society SCOR grant (S.D.N.), a Leukemia Lymphoma Society fellowship (L.W.), an Empire State Stem Cell Scholar award (L.W.), and a New York State Stem Cell Science grant (S.D.N.).

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg