Skip to main content

Advertisement

SpringerLink
Log in

Molecular pathogenesis of core binding factor leukemia: current knowledge and future prospects

  • Progress in Hematology
  • Signaling and transcription in the development of leukemia
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

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.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. 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.

    Article  CAS  PubMed  Google Scholar 

  2. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Speck NA, Gilliland DG. Core-binding factors in haematopoiesis and leukaemia. Nat Rev Cancer. 2002;2:502–13.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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.

    Article  CAS  PubMed  Google Scholar 

  16. 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.

    Article  CAS  PubMed  Google Scholar 

  17. 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.

    CAS  PubMed  Google Scholar 

  18. 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.

    Article  CAS  PubMed  Google Scholar 

  19. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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.

    Article  CAS  PubMed  Google Scholar 

  22. 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.

    Article  CAS  PubMed  Google Scholar 

  23. 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.

    Article  CAS  PubMed  Google Scholar 

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed  Google Scholar 

  26. 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.

    Article  CAS  PubMed  Google Scholar 

  27. 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.

    Article  CAS  PubMed  Google Scholar 

  28. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. 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.

    Article  CAS  PubMed  Google Scholar 

  31. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  34. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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.

    CAS  PubMed  Google Scholar 

  36. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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.

    Article  CAS  PubMed  Google Scholar 

  39. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 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.

    Article  CAS  PubMed  Google Scholar 

  42. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  43. 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.

    Article  CAS  PubMed  Google Scholar 

  44. 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.

    Article  CAS  PubMed  Google Scholar 

  45. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  47. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 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.

    Article  CAS  PubMed  Google Scholar 

  51. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 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.

    Article  CAS  PubMed  Google Scholar 

  54. 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.

    Article  CAS  PubMed  Google Scholar 

  55. 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.

    Article  CAS  PubMed  Google Scholar 

  56. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 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.

    Article  CAS  PubMed  Google Scholar 

  58. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 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.

    Article  CAS  PubMed  Google Scholar 

  62. 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.

    Article  CAS  PubMed  Google Scholar 

  63. 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.

    Article  CAS  PubMed  Google Scholar 

  64. 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.

    Article  CAS  PubMed  Google Scholar 

  65. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 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.

    Article  CAS  PubMed  Google Scholar 

  67. 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.

    Article  CAS  PubMed  Google Scholar 

  68. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 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.

    Article  CAS  PubMed  Google Scholar 

  71. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Gilliland DG, Jordan CT, Felix CA, The molecular basis of leukemia. Hematology Am Soc Hematol Educ Program 2004;80–97.

  73. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 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.

    Article  CAS  PubMed  Google Scholar 

  75. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 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.

    Article  CAS  PubMed  Google Scholar 

  78. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Park S, Speck NA, Bushweller JH. The role of CBFbeta in AML1-ETO’s activity. Blood. 2009;114:2849–50.

    Article  CAS  PubMed  Google Scholar 

  80. Kwok C, Zeisig BB, Dong S, So CW. The role of CBFbeta in AML1-ETO’s activity. Blood. 2010;115:3176–7.

    Article  CAS  PubMed  Google Scholar 

  81. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work is supported by NIH Grant CA118319 (JCM) and by JSPS Postdoctoral Fellowship for Research Abroad (SG).

Author information

Authors and Affiliations

  1. Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Susumu Goyama & James C. Mulloy

Authors
  1. Susumu Goyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James C. Mulloy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James C. Mulloy.

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-011-0858-z

Keywords

Search

Navigation