Abstract
Core binding factor (CBF) acute myeloid leukemia (AML) is the most common cytogenetic subtype of AML, defined by the presence of t(8;21) or inv(16)/t(16;16). The chromosomal aberrations create AML1-ETO and CBFβ-MYH11 fusion genes that disrupt the functions of CBF, an essential transcription factor in hematopoiesis. Despite the relatively good outcome of patients with CBF-AML, only approximately half of the patients are cured with current therapy, indicating the need for improved therapeutic strategies. In this review, we summarize current knowledge regarding altered transcriptional regulation, aberrant signaling pathways, and cooperating genetic events in CBF leukemia, and discuss challenges ahead for translating these findings into the clinic.
Similar content being viewed by others
References
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;84:321–30.
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;93:3444–9.
Wang Q, Stacy T, Miller JD, Lewis AF, Gu TL, Huang X, et al. The CBFbeta subunit is essential for CBFalpha2 (AML1) function in vivo. Cell. 1996;87:697–708.
Sasaki K, Yagi H, Bronson RT, Tominaga K, Matsunashi T, Deguchi K, et al. Absence of fetal liver hematopoiesis in mice deficient in transcriptional coactivator core binding factor beta. Proc Natl Acad Sci USA. 1996;93:12359–63.
Speck NA, Gilliland DG. Core-binding factors in haematopoiesis and leukaemia. Nat Rev Cancer. 2002;2:502–13.
Wakui M, Kuriyama K, Miyazaki Y, Hata T, Taniwaki M, Ohtake S, et al. Diagnosis of acute myeloid leukemia according to the WHO classification in the Japan Adult Leukemia Study Group AML-97 protocol. Int J Hematol. 2008;87:144–51.
Schlenk RF, Benner A, Krauter J, Buchner T, Sauerland C, Ehninger G, et al. Individual patient data-based meta-analysis of patients aged 16 to 60 years with core binding factor acute myeloid leukemia: a survey of the German Acute Myeloid Leukemia Intergroup. J Clin Oncol. 2004;22:3741–50.
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;95:10860–5.
Amann JM, Nip J, Strom DK, Lutterbach B, Harada H, Lenny N, et al. ETO, a target of t(8;21) in acute leukemia, makes distinct contacts with multiple histone deacetylases and binds mSin3A through its oligomerization domain. Mol Cell Biol. 2001;21:6470–83.
Lutterbach B, Westendorf JJ, Linggi B, Patten A, Moniwa M, Davie JR, et al. ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors. Mol Cell Biol. 1998;18:7176–84.
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;18:7185–91.
Lukasik SM, Zhang L, Corpora T, Tomanicek S, Li Y, Kundu M, et al. Altered affinity of CBF beta-SMMHC for Runx1 explains its role in leukemogenesis. Nat Struct Biol. 2002;9:674–9.
Lutterbach B, Hou Y, Durst KL, Hiebert SW. The inv(16) encodes an acute myeloid leukemia 1 transcriptional corepressor. Proc Natl Acad Sci USA. 1999;96:12822–7.
Durst KL, Lutterbach B, Kummalue T, Friedman AD, Hiebert SW. The inv(16) fusion protein associates with corepressors via a smooth muscle myosin heavy-chain domain. Mol Cell Biol. 2003;23:607–19.
Shigesada K, van de Sluis B, Liu PP. Mechanism of leukemogenesis by the inv(16) chimeric gene CBFB/PEBP2B-MHY11. Oncogene. 2004;23:4297–307.
Yergeau DA, Hetherington CJ, Wang Q, Zhang P, Sharpe AH, Binder M, et al. Embryonic lethality and impairment of haematopoiesis in mice heterozygous for an AML1-ETO fusion gene. Nat Genet. 1997;15:303–6.
Okuda T, Cai Z, Yang S, Lenny N, Lyu CJ, van Deursen JM, et al. Expression of a knocked-in AML1-ETO leukemia gene inhibits the establishment of normal definitive hematopoiesis and directly generates dysplastic hematopoietic progenitors. Blood. 1998;91:3134–43.
Castilla LH, Garrett L, Adya N, Orlic D, Dutra A, Anderson S, et al. The fusion gene Cbfb-MYH11 blocks myeloid differentiation and predisposes mice to acute myelomonocytic leukaemia. Nat Genet. 1999;23:144–6.
Kamikubo Y, Zhao L, Wunderlich M, Corpora T, Hyde RK, Paul TA, et al. Accelerated leukemogenesis by truncated CBF beta-SMMHC defective in high-affinity binding with RUNX1. Cancer Cell. 2010;17:455–68.
Hyde RK, Kamikubo Y, Anderson S, Kirby M, Alemu L, Zhao L, et al. Cbfb/Runx1 repression-independent blockage of differentiation and accumulation of Csf2rb-expressing cells by Cbfb-MYH11. Blood. 2010;115:1433–43.
Tang JL, Hou HA, Chen CY, Liu CY, Chou WC, Tseng MH, et al. AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations. Blood. 2009;114:5352–61.
Schnittger S, Dicker F, Kern W, Wendland N, Sundermann J, Alpermann T, et al. RUNX1 mutations are frequent in de novo AML with non complex karyotype and confer an unfavourable prognosis. Blood. 2011;117:2348–57.
Vangala RK, Heiss-Neumann MS, Rangatia JS, Singh SM, Schoch C, Tenen DG, et al. The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia. Blood. 2003;101:270–7.
Pabst T, Mueller BU, Harakawa N, Schoch C, Haferlach T, Behre G, et al. AML1-ETO downregulates the granulocytic differentiation factor C/EBPalpha in t(8;21) myeloid leukemia. Nat Med. 2001;7:444–51.
Helbling D, Mueller BU, Timchenko NA, Schardt J, Eyer M, Betts DR, et al. CBFB-SMMHC is correlated with increased calreticulin expression and suppresses the granulocytic differentiation factor CEBPA in AML with inv(16). Blood. 2005;106:1369–75.
Choi Y, Elagib KE, Delehanty LL, Goldfarb AN. Erythroid inhibition by the leukemic fusion AML1-ETO is associated with impaired acetylation of the major erythroid transcription factor GATA-1. Cancer Res. 2006;66:2990–6.
Linggi B, Muller-Tidow C, van de Locht L, Hu M, Nip J, Serve H, et al. The t(8;21) fusion protein, AML1 ETO, specifically represses the transcription of the p14(ARF) tumor suppressor in acute myeloid leukemia. Nat Med. 2002;8:743–50.
Yang G, Khalaf W, van de Locht L, Jansen JH, Gao M, Thompson MA, et al. Transcriptional repression of the Neurofibromatosis-1 tumor suppressor by the t(8;21) fusion protein. Mol Cell Biol. 2005;25:5869–79.
Markus J, Garin MT, Bies J, Galili N, Raza A, Thirman MJ, et al. Methylation-independent silencing of the tumor suppressor INK4b (p15) by CBFbeta-SMMHC in acute myelogenous leukemia with inv(16). Cancer Res. 2007;67:992–1000.
Cheng CK, Li L, Cheng SH, Lau KM, Chan NP, Wong RS, et al. Transcriptional repression of the RUNX3/AML2 gene by the t(8;21) and inv(16) fusion proteins in acute myeloid leukemia. Blood. 2008;112:3391–402.
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;109:4392–8.
Berg T, Fliegauf M, Burger J, Staege MS, Liu S, Martinez N, et al. Transcriptional upregulation of p21/WAF/Cip1 in myeloid leukemic blasts expressing AML1-ETO. Haematologica. 2008;93:1728–33.
Viale A, De Franco F, Orleth A, Cambiaghi V, Giuliani V, Bossi D, et al. Cell-cycle restriction limits DNA damage and maintains self-renewal of leukaemia stem cells. Nature. 2009;457:51–6.
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;93:14059–64.
Banker DE, Radich J, Becker A, Kerkof K, Norwood T, Willman C, et al. The t(8;21) translocation is not consistently associated with high Bcl-2 expression in de novo acute myeloid leukemias of adults. Clin Cancer Res. 1998;4:3051–62.
Alcalay M, Meani N, Gelmetti V, Fantozzi A, Fagioli M, Orleth A, et al. Acute myeloid leukemia fusion proteins deregulate genes involved in stem cell maintenance and DNA repair. J Clin Invest. 2003;112:1751–61.
Krejci O, Wunderlich M, Geiger H, Chou FS, Schleimer D, Jansen M, et al. p53 signaling in response to increased DNA damage sensitizes AML1-ETO cells to stress-induced death. Blood. 2008;111:2190–9.
Zhang J, Kalkum M, Yamamura S, Chait BT, Roeder RG. E protein silencing by the leukemogenic AML1-ETO fusion protein. Science. 2004;305:1286–9.
Plevin MJ, Zhang J, Guo C, Roeder RG, Ikura M. The acute myeloid leukemia fusion protein AML1-ETO targets E proteins via a paired amphipathic helix-like TBP-associated factor homology domain. Proc Natl Acad Sci USA. 2006;103:10242–7.
Figueroa ME, Lugthart S, Li Y, Erpelinck-Verschueren C, Deng X, Christos PJ, et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell. 2010;17:13–27.
Liu S, Shen T, Huynh L, Klisovic MI, Rush LJ, Ford JL, et al. Interplay of RUNX1/MTG8 and DNA methyltransferase 1 in acute myeloid leukemia. Cancer Res. 2005;65:1277–84.
Alvarez S, Suela J, Valencia A, Fernandez A, Wunderlich M, Agirre X, et al. DNA methylation profiles and their relationship with cytogenetic status in adult acute myeloid leukemia. PLoS One. 2010;5:e12197.
Fazi F, Racanicchi S, Zardo G, Starnes LM, Mancini M, Travaglini L, et al. Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein. Cancer Cell. 2007;12:457–66.
Jongen-Lavrencic M, Sun SM, Dijkstra MK, Valk PJ, Lowenberg B. MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia. Blood. 2008;111:5078–85.
Li Z, Lu J, Sun M, Mi S, Zhang H, Luo RT, et al. Distinct microRNA expression profiles in acute myeloid leukemia with common translocations. Proc Natl Acad Sci USA. 2008;105:15535–40.
Muller-Tidow C, Steffen B, Cauvet T, Tickenbrock L, Ji P, Diederichs S, et al. Translocation products in acute myeloid leukemia activate the Wnt signaling pathway in hematopoietic cells. Mol Cell Biol. 2004;24:2890–904.
Mulloy JC, Jankovic V, Wunderlich M, Delwel R, Cammenga J, Krejci O, et al. AML1-ETO fusion protein up-regulates TRKA mRNA expression in human CD34 + cells, allowing nerve growth factor-induced expansion. Proc Natl Acad Sci USA. 2005;102:4016–21.
Yeh JR, Munson KM, Elagib KE, Goldfarb AN, Sweetser DA, Peterson RT. Discovering chemical modifiers of oncogene-regulated hematopoietic differentiation. Nat Chem Biol. 2009;5:236–43.
Sinenko SA, Hung T, Moroz T, Tran QM, Sidhu S, Cheney MD, et al. Genetic manipulation of AML1-ETO-induced expansion of hematopoietic precursors in a Drosophila model. Blood. 2010;116:4612–20.
Sun X, Zhang W, Ramdas L, Stivers DN, Jones DM, Kantarjian HM, et al. Comparative analysis of genes regulated in acute myelomonocytic leukemia with and without inv(16)(p13q22) using microarray techniques, real-time PCR, immunohistochemistry, and flow cytometry immunophenotyping. Mod Pathol. 2007;20:811–20.
Wang Y, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z, et al. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science. 2010;327:1650–3.
Yuan Y, Zhou L, Miyamoto T, Iwasaki H, Harakawa N, Hetherington CJ, et al. 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;98:10398–403.
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;1:63–74.
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;99:15–23.
Mulloy JC, Cammenga J, Berguido FJ, Wu K, Zhou P, Comenzo RL, et al. Maintaining the self-renewal and differentiation potential of human CD34+ hematopoietic cells using a single genetic element. Blood. 2003;102:4369–76.
Wunderlich M, Krejci O, Wei J, Mulloy JC. Human CD34+ cells expressing the inv(16) fusion protein exhibit a myelomonocytic phenotype with greatly enhanced proliferative ability. Blood. 2006;108:1690–7.
Tonks A, Pearn L, Tonks AJ, Pearce L, Hoy T, Phillips S, et al. The AML1-ETO fusion gene promotes extensive self-renewal of human primary erythroid cells. Blood. 2003;101:624–32.
Mrozek K, Marcucci G, Paschka P, Bloomfield CD. Advances in molecular genetics and treatment of core-binding factor acute myeloid leukemia. Curr Opin Oncol. 2008;20:711–8.
Jones D, Yao H, Romans A, Dando C, Pierce S, Borthakur G, et al. Modeling interactions between leukemia-specific chromosomal changes. Somatic mutations, and gene expression patterns during progression of core-binding factor leukemias. Genes Chromosomes Cancer. 2010;49:182–91.
Dayyani F, Wang J, Yeh JR, Ahn EY, Tobey E, Zhang DE, et al. Loss of TLE1 and TLE4 from the del(9q) commonly deleted region in AML cooperates with AML1-ETO to affect myeloid cell proliferation and survival. Blood. 2008;111:4338–47.
Carella C, Bonten J, Sirma S, Kranenburg TA, Terranova S, Klein-Geltink R, et al. MN1 overexpression is an important step in the development of inv(16) AML. Leukemia. 2007;21:1679–90.
Boissel N, Leroy H, Brethon B, Philippe N, de Botton S, Auvrignon A, et al. Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML). Leukemia. 2006;20:965–70.
Carlsson IB, Laitinen MP, Scott JE, Louhio H, Velentzis L, Tuuri T, et al. Kit ligand and c-Kit are expressed during early human ovarian follicular development and their interaction is required for the survival of follicles in long-term culture. Reproduction. 2006;131:641–9.
Shih LY, Liang DC, Huang CF, Chang YT, Lai CL, Lin TH, et al. Cooperating mutations of receptor tyrosine kinases and Ras genes in childhood core-binding factor acute myeloid leukemia and a comparative analysis on paired diagnosis and relapse samples. Leukemia. 2008;22:303–7.
Wang YY, Zhao LJ, Wu CF, Liu P, Shi L, Liang Y, et al. C-KIT mutation cooperates with full-length AML1-ETO to induce acute myeloid leukemia in mice. Proc Natl Acad Sci USA. 2011;108:2450–5.
Schnittger S, Schoch C, Dugas M, Kern W, Staib P, Wuchter C, 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.
Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99:4326–35.
Kim HG, Kojima K, Swindle CS, Cotta CV, Huo Y, Reddy V, et al. FLT3-ITD cooperates with inv(16) to promote progression to acute myeloid leukemia. Blood. 2008;111:1567–74.
Schessl C, Rawat VP, Cusan M, Deshpande A, Kohl TM, Rosten PM, et al. The AML1-ETO fusion gene and the FLT3 length mutation collaborate in inducing acute leukemia in mice. J Clin Invest. 2005;115:2159–68.
Bacher U, Haferlach T, Schoch C, Kern W, Schnittger S. Implications of NRAS mutations in AML: a study of 2502 patients. Blood. 2006;107:3847–53.
Chou FS, Wunderlich M, Griesinger A, Mulloy JC. NRASG12D induces stepwise transformation in preleukemic human umbilical cord blood cultures expressing the AML1-ETO fusion gene. Blood. 2011;117:2237–40.
Gilliland DG, Jordan CT, Felix CA, The molecular basis of leukemia. Hematology Am Soc Hematol Educ Program 2004;80–97.
Yan M, Burel SA, Peterson LF, Kanbe E, Iwasaki H, Boyapati A, et al. Deletion of an AML1-ETO C-terminal NcoR/SMRT-interacting region strongly induces leukemia development. Proc Natl Acad Sci USA. 2004;101:17186–91.
Yan M, Kanbe E, Peterson LF, Boyapati A, Miao Y, Wang Y, et al. A previously unidentified alternatively spliced isoform of t(8;21) transcript promotes leukemogenesis. Nat Med. 2006;12:945–9.
Zuber J, Radtke I, Pardee TS, Zhao Z, Rappaport AR, Luo W, et al. Mouse models of human AML accurately predict chemotherapy response. Genes Dev. 2009;23:877–89.
Roudaia L, Cheney MD, Manuylova E, Chen W, Morrow M, Park S, et al. CBFbeta is critical for AML1-ETO and TEL-AML1 activity. Blood. 2009;113:3070–9.
Gorczynski MJ, Grembecka J, Zhou Y, Kong Y, Roudaia L, Douvas MG, et al. Allosteric inhibition of the protein-protein interaction between the leukemia-associated proteins Runx1 and CBFbeta. Chem Biol. 2007;14:1186–97.
Kwok C, Zeisig BB, Qiu J, Dong S, So CW. Transforming activity of AML1-ETO is independent of CBFbeta and ETO interaction but requires formation of homo-oligomeric complexes. Proc Natl Acad Sci USA. 2009;106:2853–8.
Park S, Speck NA, Bushweller JH. The role of CBFbeta in AML1-ETO’s activity. Blood. 2009;114:2849–50.
Kwok C, Zeisig BB, Dong S, So CW. The role of CBFbeta in AML1-ETO’s activity. Blood. 2010;115:3176–7.
Davis ME, Zuckerman JE, Choi CH, Seligson D, Tolcher A, Alabi CA, et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature. 2010;464:1067–70.
Mulloy JC, Wunderlich M, Zheng Y, Wei J. Transforming human blood stem and progenitor cells: a new way forward in leukemia modeling. Cell Cycle. 2008;7:3314–9.
Wunderlich M, Mulloy JC. Model systems for examining effects of leukemia-associated oncogenes in primary human CD34+ cells via retroviral transduction. Methods Mol Biol. 2009;538:263–85.
Acknowledgments
This work is supported by NIH Grant CA118319 (JCM) and by JSPS Postdoctoral Fellowship for Research Abroad (SG).
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Goyama, S., Mulloy, J.C. Molecular pathogenesis of core binding factor leukemia: current knowledge and future prospects. Int J Hematol 94, 126–133 (2011). https://doi.org/10.1007/s12185-011-0858-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12185-011-0858-z