Proleukemic RUNX1 and CBFβ Mutations in the Pathogenesis of Acute Leukemia

Part of the Cancer Treatment and Research book series (CTAR, volume 145)


The existence of non-random mutations in critical regulators of cell growth and differentiation is a recurring theme in cancer pathogenesis and provides the basis for our modern, molecular approach to the study and treatment of malignant diseases. Nowhere is this more true than in the study of leukemogenesis, where research has converged upon a critical group of genes involved in hematopoietic stem and progenitor cell self-renewal and fate specification. Prominent among these is the heterodimeric transcriptional regulator, RUNX1/CBFβ. RUNX1 is a site-specific DNA-binding protein whose consensus response element is found in the promoters of many hematopoietically relevant genes. CBFβ interacts with RUNX1, stabilizing its interaction with DNA to promote the actions of RUNX1/CBFβ in transcriptional control. Both the RUNX1 and the CBFβ genes participate in proleukemic chromosomal alterations. Together they contribute to approximately one-third of acute myelogenous leukemia (AML) and one-quarter of acute lymphoblastic leukemia (ALL) cases, making RUNX1 and CBFβ the most frequently affected genes known in the pathogenesis of acute leukemia. Investigating the mechanisms by which RUNX1, CBFβ, and their proleukemic fusion proteins influence leukemogenesis has contributed greatly to our understanding of both normal and malignant hematopoiesis. Here we present an overview of the structural features of RUNX1/CBFβ and their derivatives, their roles in transcriptional control, and their contributions to normal and malignant hematopoiesis.


Acute Myeloid Leukemia Normal Hematopoiesis Definitive Hematopoiesis Cytoplasmic Sequestration Central Nervous System Hemorrhage 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors greatly appreciate the thoughtful comments and support from members of the Hiebert Laboratory during the preparation of this monograph.


  1. 1.
    Adya N, Stacy T, Speck NA, Liu PP. The leukemic protein core binding factor beta (CBFbeta)-smooth-muscle myosin heavy chain sequesters CBFalpha2 into cytoskeletal filaments and aggregates. Mol Cell Biol. 1998;18(12):7432–7443.PubMedGoogle Scholar
  2. 2.
    Adya N, Castilla LH, Liu PP. Function of CBFbeta/Bro proteins. Semin Cell Dev Biol. 2000;11(5):361–368.PubMedCrossRefGoogle Scholar
  3. 3.
    Ahn MY, Huang G, Bae SC, Wee HJ, Kim WY, Ito Y. Negative regulation of granulocytic differentiation in the myeloid precursor cell line 32Dcl3 by ear-2, a mammalian homolog of Drosophila seven-up, and a chimeric leukemogenic gene, AML1/ETO. Proc Natl Acad Sci USA. 17 1998;95(4):1812–1817.PubMedCrossRefGoogle Scholar
  4. 4.
    Amann JM, Nip J, Strom DK, 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(19):6470–6483.PubMedCrossRefGoogle Scholar
  5. 5.
    Amann JM, Chyla BJ, Ellis TC, et al. Mtgr1 is a transcriptional corepressor that is required for maintenance of the secretory cell lineage in the small intestine. Mol Cell Biol. 2005;25(21):9576–9585.PubMedCrossRefGoogle Scholar
  6. 6.
    Andreasson P, Schwaller J, Anastasiadou E, Aster J, Gilliland DG. The expression of ETV6/CBFA2 (TEL/AML1) is not sufficient for the transformation of hematopoietic cell lines in vitro or the induction of hematologic disease in vivo. Cancer Genet Cytogenet. 2001;130(2):93–104.PubMedCrossRefGoogle Scholar
  7. 7.
    Aronson BD, Fisher AL, Blechman K, Caudy M, Gergen JP. Groucho-dependent and -independent repression activities of Runt domain proteins. Mol Cell Biol. 1997;17(9):5581–5587.PubMedGoogle Scholar
  8. 8.
    Asimakopoulos FA, Green AR. Deletions of chromosome 20q and the pathogenesis of myeloproliferative disorders. Br J Haematol. 1996;95(2):219–226.PubMedCrossRefGoogle Scholar
  9. 9.
    Bae SC, Yamaguchi-Iwai Y, Ogawa E, et al. Isolation of PEBP2 alpha B cDNA representing the mouse homolog of human acute myeloid leukemia gene, AML1. Oncogene. 1993;8(3):809–814.PubMedGoogle Scholar
  10. 10.
    Berardi MJ, Sun C, Zehr M, et al. The Ig fold of the core binding factor alpha Runt domain is a member of a family of structurally and functionally related Ig-fold DNA-binding domains. Structure. 1999;7(10):1247–1256.PubMedCrossRefGoogle Scholar
  11. 11.
    Bohlander SK. ETV6: a versatile player in leukemogenesis. Semin Cancer Biol. 2005;15(3):162–174.PubMedCrossRefGoogle Scholar
  12. 12.
    Bresnick EH, Chu J, Christensen HM, Lin B, Norton J. Linking Notch signaling, chromatin remodeling, and T-cell leukemogenesis. J Cell Biochem Suppl. 2000;(suppl 35):46–53.Google Scholar
  13. 13.
    Castilla LH, Wijmenga C, Wang Q, et al. Failure of embryonic hematopoiesis and lethal hemorrhages in mouse embryos heterozygous for a knocked-in leukemia gene CBFB-MYH11. Cell. 1996;87(4):687–696.PubMedCrossRefGoogle Scholar
  14. 14.
    Castilla LH, Perrat P, Martinez NJ, et al. Identification of genes that synergize with Cbfb-MYH11 in the pathogenesis of acute myeloid leukemia. Proc Natl Acad Sci USA. 2004;101(14):4924–4929.PubMedCrossRefGoogle Scholar
  15. 15.
    Castilla LH, Garrett L, Adya N, et al. The fusion gene Cbfb-MYH11 blocks myeloid differentiation and predisposes mice to acute myelomonocytic leukaemia. Nat Genet. 1999;23(2):144–146.PubMedCrossRefGoogle Scholar
  16. 16.
    Chakrabarti SR, Nucifora G. The leukemia-associated gene TEL encodes a transcription repressor which associates with SMRT and mSin3A. Biochem Biophys Res Commun. 1999;264(3):871–877.PubMedCrossRefGoogle Scholar
  17. 17.
    Chevallier N, Corcoran CM, Lennon C, et al. ETO protein of t(8;21) AML is a corepressor for Bcl-6 B-cell lymphoma oncoprotein. Blood. 2004;103(4):1454–1463.PubMedCrossRefGoogle Scholar
  18. 18.
    Coffman JA. Runx transcription factors and the developmental balance between cell proliferation and differentiation. Cell Biol Int. 2003;27(4):315–324.PubMedCrossRefGoogle Scholar
  19. 19.
    Davis JN, Williams BJ, Herron JT, Galiano FJ, Meyers S. ETO-2, a new member of the ETO-family of nuclear proteins. Oncogene. 1999;18(6):1375–1383.PubMedCrossRefGoogle Scholar
  20. 20.
    Davis JN, McGhee L, Meyers S. The ETO (MTG8) gene family. Gene. 2003;303:1–10.PubMedCrossRefGoogle Scholar
  21. 21.
    de la Chapelle A, Lahtinen R. Chromosome 16 and bone-marrow eosinophilia. N Engl J Med. 1983;309(22):1394.PubMedGoogle Scholar
  22. 22.
    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(2):607–619.PubMedCrossRefGoogle Scholar
  23. 23.
    Erman B, Cortes M, Nikolajczyk BS, Speck NA, Sen R. ETS-core binding factor: a common composite motif in antigen receptor gene enhancers. Mol Cell Biol. 1998;18(3):1322–1330.PubMedGoogle Scholar
  24. 24.
    Fenrick R, Amann JM, Lutterbach B, et al. Both TEL and AML-1 contribute repression domains to the t(12;21) fusion protein. Mol Cell Biol. 1999;19(10):6566–6574.PubMedGoogle Scholar
  25. 25.
    Ford AM, Bennett CA, Price CM, Bruin MC, Van Wering ER, Greaves M. Fetal origins of the TEL-AML1 fusion gene in identical twins with leukemia. Proc Natl Acad Sci USA. 1998;95(8):4584–4588.PubMedCrossRefGoogle Scholar
  26. 26.
    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. Oncogene. 1995;11(12):2667–2674.PubMedGoogle Scholar
  27. 27.
    Gamou T, Kitamura E, Hosoda F, et al. The partner gene of AML1 in t(16;21) myeloid malignancies is a novel member of the MTG8(ETO) family. Blood. 1998;91(11):4028–4037.PubMedGoogle Scholar
  28. 28.
    Ganly P, Walker LC, Morris CM. Familial mutations of the transcription factor RUNX1 (AML1, CBFA2) predispose to acute myeloid leukemia. Leuk Lymphoma. 2004;45(1):1–10.PubMedCrossRefGoogle Scholar
  29. 29.
    Gergen JP, Butler BA. Isolation of the Drosophila segmentation gene runt and analysis of its expression during embryogenesis. Genes Dev. 1988;2(9):1179–1193.PubMedCrossRefGoogle Scholar
  30. 30.
    Golub TR, Barker GF, Bohlander SK, et al. Fusion of the TEL gene on 12p13 to the AML1 gene on 21q22 in acute lymphoblastic leukemia. Proc Natl Acad Sci USA. 1995;92(11):4917–4921.PubMedCrossRefGoogle Scholar
  31. 31.
    Grosveld F, Rodriguez P, Meier N, et al. Isolation and characterization of hematopoietic transcription factor complexes by in vivo biotinylation tagging and mass spectrometry. Ann N Y Acad Sci. 2005;1054:55–67.PubMedCrossRefGoogle Scholar
  32. 32.
    Hernandez-Munain C, Krangel MS. Regulation of the T-cell receptor delta enhancer by functional cooperation between c-Myb and core-binding factors. Mol Cell Biol. 1994;14(1):473–483.PubMedGoogle Scholar
  33. 33.
    Hiebert SW, Lutterbach B, Amann J. Role of co-repressors in transcriptional repression mediated by the t(8;1), t(16;21), t(12;21), and inv(16) fusion proteins. Curr Opin Hematol. 2001;8(4):197–200.PubMedCrossRefGoogle Scholar
  34. 34.
    Hiebert SW, Sun W, Davis JN, et al. The t(12;21) translocation converts AML-1B from an activator to a repressor of transcription. Mol Cell Biol. 1996;16(4):1349–1355.PubMedGoogle Scholar
  35. 35.
    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.PubMedCrossRefGoogle Scholar
  36. 36.
    Hoogeveen AT, Rossetti S, Stoyanova V, et al. The transcriptional corepressor MTG16a contains a novel nucleolar targeting sequence deranged in t (16; 21)-positive myeloid malignancies. Oncogene. 2002;21(43):6703–6712.PubMedCrossRefGoogle Scholar
  37. 37.
    Huang G, Shigesada K, Ito K, Wee HJ, Yokomizo T, Ito Y. Dimerization with PEBP2beta protects RUNX1/AML1 from ubiquitin-proteasome-mediated degradation. Embo J. 2001;20(4):723–733.PubMedCrossRefGoogle Scholar
  38. 38.
    Huang G, Shigesada K, Wee HJ, Liu PP, Osato M, Ito Y. Molecular basis for a dominant inactivation of RUNX1/AML1 by the leukemogenic inversion 16 chimera. Blood. 2004;103(8):3200–3207.PubMedCrossRefGoogle Scholar
  39. 39.
    Hug BA, Lazar MA. ETO interacting proteins. Oncogene. 2004;23(24):4270–4274.PubMedCrossRefGoogle Scholar
  40. 40.
    Javed A, Guo B, Hiebert S, et al. Groucho/TLE/R-esp proteins associate with the nuclear matrix and repress RUNX (CBF(alpha)/AML/PEBP2(alpha)) dependent activation of tissue-specific gene transcription. J Cell Sci. 2000;113 (Pt 12):2221–2231.PubMedGoogle Scholar
  41. 41.
    Kamachi Y, Ogawa E, Asano M, et al. Purification of a mouse nuclear factor that binds to both the A and B cores of the polyomavirus enhancer. J Virol. 1990;64(10):4808–4819.PubMedGoogle Scholar
  42. 42.
    Kania MA, Bonner AS, Duffy JB, Gergen JP. The Drosophila segmentation gene runt encodes a novel nuclear regulatory protein that is also expressed in the developing nervous system. Genes Dev. 1990;4(10):1701–1713.PubMedCrossRefGoogle Scholar
  43. 43.
    Kuo YH, Landrette SF, Heilman SA, et al. Cbf beta-SMMHC induces distinct abnormal myeloid progenitors able to develop acute myeloid leukemia. Cancer Cell. 2006;9(1):57–68.PubMedCrossRefGoogle Scholar
  44. 44.
    Le Beau MM, Larson RA, Bitter MA, Vardiman JW, Golomb HM, Rowley JD. Association of an inversion of chromosome 16 with abnormal marrow eosinophils in acute myelomonocytic leukemia. A unique cytogenetic-clinicopathological association. N Engl J Med. 1983;309(11):630–636.PubMedCrossRefGoogle Scholar
  45. 45.
    Lenny N, Westendorf JJ, Hiebert SW. Transcriptional regulation during myelopoiesis. Mol Biol Rep. 1997;24(3):157–168.PubMedCrossRefGoogle Scholar
  46. 46.
    Leroy H, Roumier C, Grardel-Duflos N, et al. Unlike AML1, CBFbeta gene is not deregulated by point mutations in acute myeloid leukemia and in myelodysplastic syndromes. Blood. 2002;99(10):3848–3850.PubMedCrossRefGoogle Scholar
  47. 47.
    Levanon D, Negreanu V, Bernstein Y, Bar-Am I, Avivi L, Groner Y. AML1, AML2, and AML3, the human members of the runt domain gene-family: cDNA structure, expression, and chromosomal localization. Genomics. 1994;23(2):425–432.PubMedCrossRefGoogle Scholar
  48. 48.
    Levanon D, Goldstein RE, Bernstein Y, et al. Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho corepressors. Proc Natl Acad Sci USA. 1998;95(20):11590–11595.PubMedCrossRefGoogle Scholar
  49. 49.
    Linggi B, Muller-Tidow C, van de Locht L, 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(7):743–750.PubMedCrossRefGoogle Scholar
  50. 50.
    Liu P, Tarle SA, Hajra A, et al. Fusion between transcription factor CBF beta/PEBP2 beta and a myosin heavy chain in acute myeloid leukemia. Science. 1993;261(5124):1041–1044.PubMedCrossRefGoogle Scholar
  51. 51.
    Liu Y, Cheney MD, Gaudet JJ, et al. The tetramer structure of the Nervy homology two domain, NHR2, is critical for AML1/ETO's activity. Cancer Cell. 2006;9(4):249–260.PubMedCrossRefGoogle Scholar
  52. 52.
    Lu J, Maruyama M, Satake M, et al. Subcellular localization of the alpha and beta subunits of the acute myeloid leukemia-linked transcription factor PEBP2/CBF. Mol Cell Biol. 1995;15(3):1651–1661.PubMedGoogle Scholar
  53. 53.
    Lutterbach B, Hiebert SW. Role of the transcription factor AML-1 in acute leukemia and hematopoietic differentiation. Gene. 21 2000;245(2):223–235.PubMedCrossRefGoogle Scholar
  54. 54.
    Lutterbach B, Westendorf JJ, Linggi B, Isaac S, Seto E, Hiebert SW. A mechanism of repression by acute myeloid leukemia-1, the target of multiple chromosomal translocations in acute leukemia. J Biol Chem. 2000;275(1):651–656.PubMedCrossRefGoogle Scholar
  55. 55.
    Lutterbach B, Westendorf JJ, Linggi B, 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(12):7176–7184.PubMedGoogle Scholar
  56. 56.
    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(22):12822–12827.PubMedCrossRefGoogle Scholar
  57. 57.
    Lutterbach B, Sun D, Schuetz J, Hiebert SW. The MYND motif is required for repression of basal transcription from the multidrug resistance 1 promoter by the t(8;21) fusion protein. Mol Cell Biol. 1998;18(6):3604–3611.PubMedGoogle Scholar
  58. 58.
    Mao S, Frank RC, Zhang J, Miyazaki Y, Nimer SD. Functional and physical interactions between AML1 proteins and an ETS protein, MEF: implications for the pathogenesis of t(8;21)-positive leukemias. Mol Cell Biol. 1999;19(5):3635–3644.PubMedGoogle Scholar
  59. 59.
    McGhee L, Bryan J, Elliott L, et al. Gfi-1 attaches to the nuclear matrix, associates with ETO (MTG8) and histone deacetylase proteins, and represses transcription using a TSA-sensitive mechanism. J Cell Biochem. 2003;89(5):1005–1018.PubMedCrossRefGoogle Scholar
  60. 60.
    McHale CM, Wiemels JL, Zhang L, et al. Prenatal origin of childhood acute myeloid leukemias harboring chromosomal rearrangements t(15;17) and inv(16). Blood. 2003;101(11):4640–4641.PubMedCrossRefGoogle Scholar
  61. 61.
    Schuh AH, Tipping AJ, Clark AJ, et al. ETO-2 associates with SCL in erythroid cells and megakaryocytes and provides repressor functions in erythropoiesis. Mol Cell Biol. 2005;25(23):10235–10250.PubMedCrossRefGoogle Scholar
  62. 62.
    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.PubMedGoogle Scholar
  63. 63.
    Michaud J, Wu F, Osato M, et al. In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis. Blood. 2002;99(4):1364–1372.PubMedCrossRefGoogle Scholar
  64. 64.
    Mikhail FM, Sinha KK, Saunthararajah Y, Nucifora G. Normal and transforming functions of RUNX1: a perspective. J Cell Physiol. 2006;207(3):582–593.PubMedCrossRefGoogle Scholar
  65. 65.
    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.PubMedCrossRefGoogle Scholar
  66. 66.
    Melnick AM, Westendorf JJ, Polinger A, et al. The ETO protein disrupted in t(8;21)-associated acute myeloid leukemia is a corepressor for the promyelocytic leukemia zinc finger protein. Mol Cell Biol. 2000;20(6):2075–2086.PubMedCrossRefGoogle Scholar
  67. 67.
    Moore A. Activation of TCF-dependent gene expression by the RUNX1-MTG8 fusion protein. Paper presented at: FASEB Conference on Hematologic Malignancies. 2005. Saxon's River, Vermont.Google Scholar
  68. 68.
    Moore MA. Converging pathways in leukemogenesis and stem cell self-renewal. Exp Hematol. 2005;33(7):719–737.PubMedCrossRefGoogle Scholar
  69. 69.
    Mori H, Colman SM, Xiao Z, et al. Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc Natl Acad Sci USA. 2002;99(12):8242–8427.PubMedCrossRefGoogle Scholar
  70. 70.
    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.PubMedCrossRefGoogle Scholar
  71. 71.
    Nagata T, Gupta V, Sorce D, et al. Immunoglobulin motif DNA recognition and heterodimerization of the PEBP2/CBF Runt domain. Nat Struct Biol. 1999;6(7):615–619.PubMedCrossRefGoogle Scholar
  72. 72.
    Nishimura M, Fukushima-Nakase Y, Fujita Y, et al. VWRPY motif-dependent and -independent roles of AML1/Runx1 transcription factor in murine hematopoietic development. Blood. 2004;103(2):562–570.PubMedCrossRefGoogle Scholar
  73. 73.
    Nuchprayoon I, Meyers S, Scott LM, Suzow J, Hiebert S, Friedman AD. PEBP2/CBF, the murine homolog of the human myeloid AML1 and PEBP2 beta/CBF beta proto-oncoproteins, regulates the murine myeloperoxidase and neutrophil elastase genes in immature myeloid cells. Mol Cell Biol. 994;14(8):5558–5568.PubMedGoogle Scholar
  74. 74.
    Ogawa E, Inuzuka M, Maruyama M, et al. Molecular cloning and characterization of PEBP2 beta, the heterodimeric partner of a novel Drosophila runt-related DNA binding protein PEBP2 alpha. Virology. 1993;194(1):314–331.PubMedCrossRefGoogle Scholar
  75. 75.
    Ogawa E, Maruyama M, Kagoshima H, et al. PEBP2/PEA2 represents a family of transcription factors homologous to the products of the Drosophila runt gene and the human AML1 gene. Proc Natl Acad Sci USA. 1993;90(14):6859–6863.PubMedCrossRefGoogle Scholar
  76. 76.
    Oikawa T. ETS transcription factors: possible targets for cancer therapy. Cancer Sci. 2004;95(8):626–633.PubMedCrossRefGoogle Scholar
  77. 77.
    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.PubMedCrossRefGoogle Scholar
  78. 78.
    Okuda T, Cai Z, Yang S, 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(9):3134–3143.PubMedGoogle Scholar
  79. 79.
    Peterson LF, Zhang DE. The 8;21 translocation in leukemogenesis. Oncogene. 2004;23(24):4255–4262.PubMedCrossRefGoogle Scholar
  80. 80.
    Petrovick MS, Hiebert SW, Friedman AD, Hetherington CJ, Tenen DG, Zhang DE. Multiple functional domains of AML1: PU.1 and C/EBPalpha synergize with different regions of AML1. Mol Cell Biol. 1998;18(7):3915–3925.PubMedGoogle Scholar
  81. 81.
    Preudhomme C, Warot-Loze D, Roumier C, et al. High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2 alpha B gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21. Blood. 2000;96(8):2862–2869.PubMedGoogle Scholar
  82. 82.
    Prosser HM, Wotton D, Gegonne A, et al. A phorbol ester response element within the human T-cell receptor beta-chain enhancer. Proc Natl Acad Sci USA. 1992;89(20):9934–9938.PubMedCrossRefGoogle Scholar
  83. 83.
    Redondo JM, Pfohl JL, Hernandez-Munain C, Wang S, Speck NA, Krangel MS. Indistinguishable nuclear factor binding to functional core sites of the T-cell receptor delta and murine leukemia virus enhancers. Mol Cell Biol. 1992;12(11):4817–4823.PubMedGoogle Scholar
  84. 84.
    Reilly JT. Pathogenesis of acute myeloid leukaemia and inv(16)(p13;q22): a paradigm for understanding leukaemogenesis. Br J Haematol. 2004;128:18–34.CrossRefGoogle Scholar
  85. 85.
    Rhoades KL, Hetherington CJ, Harakawa N, et al. Analysis of the role of AML1-ETO in leukemogenesis, using an inducible transgenic mouse model. Blood. 2000;96(6):2108–2115.PubMedGoogle Scholar
  86. 86.
    Rhoades KL, Hetherington CJ, Rowley JD, et al. Synergistic up-regulation of the myeloid-specific promoter for the macrophage colony-stimulating factor receptor by AML1 and the t(8;21) fusion protein may contribute to leukemogenesis. Proc Natl Acad Sci USA. 1996;93(21):11895–11900.PubMedCrossRefGoogle Scholar
  87. 87.
    Rosmarin AG, Yang Z, Resendes KK. Transcriptional regulation in myelopoiesis: hematopoietic fate choice, myeloid differentiation, and leukemogenesis. Exp Hematol. 2005;33(2):131–143.PubMedCrossRefGoogle Scholar
  88. 88.
    Rowley JD. The role of chromosome translocations in leukemogenesis. Semin Hematol. 1999;36(4 Suppl 7):59–72.PubMedGoogle Scholar
  89. 89.
    Rubnitz JE, Look AT. Molecular basis of leukemogenesis. Curr Opin Hematol. 1998;5(4):264–270.PubMedCrossRefGoogle Scholar
  90. 90.
    Schmitz N, Godde-Salz E, Gassmann W, Loffler H. Acute myelomonocytic leukemia with involvement of eosinophils and inversion of chromosome 16. Blut. 1984;48(5):263–267.PubMedGoogle Scholar
  91. 91.
    Moore AC, Amann JM, Williams CS, et al. Myeloid translocation gene family members associate with T-cell factors (TCFs) and influence TCF-dependent transcription. Mol Cell Biol. 2008;28(3):977–987.Google Scholar
  92. 92.
    Shimada H, Ichikawa H, Nakamura S, et al. Analysis of genes under the downstream control of the t(8;1) fusion protein AML1-MTG8: overexpression of the TIS11b (ERF-1, cMG1) gene induces myeloid cell proliferation in response to G-CSF. Blood. 2000;96(2):655–663.PubMedGoogle Scholar
  93. 93.
    Shimada H, Ichikawa H, Ohki M. Potential involvement of the AML1-MTG8 fusion protein in the granulocytic maturation characteristic of the t(8;21) acute myelogenous leukemia revealed by microarray analysis. Leukemia. 2002;16(5):874–885.PubMedCrossRefGoogle Scholar
  94. 94.
    Shurtleff SA, Buijs A, Behm FG, et al. TEL/AML1 fusion resulting from a cryptic t(12;21) is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent prognosis. Leukemia. 1995;9(12):1985–1989.PubMedGoogle Scholar
  95. 95.
    Speck NA, Terryl S. A new transcription factor family associated with human leukemias. Crit Rev Eukaryot Gene Expr. 1995;5(3–4):337–364.PubMedGoogle Scholar
  96. 96.
    Sun W, Graves BJ, Speck NA. Transactivation of the Moloney murine leukemia virus and T-cell receptor beta-chain enhancers by cbf and ets requires intact binding sites for both proteins. J Virol. 1995;69(8):4941–4949.PubMedGoogle Scholar
  97. 97.
    Suzow J, Friedman AD. The murine myeloperoxidase promoter contains several functional elements, one of which binds a cell type-restricted transcription factor, myeloid nuclear factor 1 (MyNF1). Mol Cell Biol. 1993;13(4):2141–2151.PubMedGoogle Scholar
  98. 98.
    Takahashi A, Satake M, Yamaguchi-Iwai Y, et al. Positive and negative regulation of granulocyte-macrophage colony-stimulating factor promoter activity by AML1-related transcription factor, PEBP2. Blood. 1995;86(2):607–616.PubMedGoogle Scholar
  99. 99.
    Tanaka K, Tanaka T, Kurokawa M, et al. The AML1/ETO(MTG8) and AML1/Evi-1 leukemia-associated chimeric oncoproteins accumulate PEBP2beta(CBFbeta) in the nucleus more efficiently than wild-type AML1. Blood. 1998;91(5):1688–1699.PubMedGoogle Scholar
  100. 100.
    Telfer JC, Hedblom EE, Anderson MK, Laurent MN, Rothenberg EV. Localization of the domains in Runx transcription factors required for the repression of CD4 in thymocytes. J Immunol. 2004;172(7):4359–4370.PubMedGoogle Scholar
  101. 101.
    Testa JR, Hogge DE, Misawa S, Zandparsa N. Chromosome 16 rearrangements in acute myelomonocytic leukemia with abnormal eosinophils. N Engl J Med. 1984;310(7):468–469.PubMedCrossRefGoogle Scholar
  102. 102.
    Uchida H, Downing JR, Miyazaki Y, Frank R, Zhang J, Nimer SD. Three distinct domains in TEL-AML1 are required for transcriptional repression of the IL-3 promoter. Oncogene. 1999;18(4):1015–1022.PubMedCrossRefGoogle Scholar
  103. 103.
    Uchida H, Zhang J, Nimer SD. AML1A and AML1B can transactivate the human IL-3 promoter. J Immunol. 1997;158(5):2251–2258.PubMedGoogle Scholar
  104. 104.
    Wang LC, Kuo F, Fujiwara Y, Gilliland DG, Golub TR, Orkin SH. Yolk sac angiogenic defect and intra-embryonic apoptosis in mice lacking the Ets-related factor TEL. Embo J. 1997;16(14):4374–4383.PubMedCrossRefGoogle Scholar
  105. 105.
    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.PubMedCrossRefGoogle Scholar
  106. 106.
    Wang Q, Stacy T, Miller JD, et al. The CBFbeta subunit is essential for CBFalpha2 (AML1) function in vivo. Cell. 1996;87(4):697–708.PubMedCrossRefGoogle Scholar
  107. 107.
    Wang S, Wang Q, Crute BE, Melnikova IN, Keller SR, Speck NA. Cloning and characterization of subunits of the T-cell receptor and murine leukemia virus enhancer core-binding factor. Mol Cell Biol. 1993;13(6):3324–3339.PubMedGoogle Scholar
  108. 108.
    Wargnier A, Legros-Maida S, Bosselut R, et al. Identification of human granzyme B promoter regulatory elements interacting with activated T-cell-specific proteins: implication of Ikaros and CBF binding sites in promoter activation. Proc Natl Acad Sci USA. 1995;92(15):6930–6934.PubMedCrossRefGoogle Scholar
  109. 109.
    Warren AJ, Bravo J, Williams RL, Rabbitts TH. Structural basis for the heterodimeric interaction between the acute leukaemia-associated transcription factors AML1 and CBFbeta. Embo J. 2000;19(12):3004–3015.PubMedCrossRefGoogle Scholar
  110. 110.
    Wessels HW, Dauwerse HG, Breuning MH, Beverstock GC. Inversion 16 and translocation (16;16) in ANLL M4eo break in the same subregion of the short arm of chromosome 16. Cancer Genet Cytogenet. 1991;57(2):225–228.PubMedCrossRefGoogle Scholar
  111. 111.
    Westendorf JJ, Yamamoto CM, Lenny N, Downing JR, Selsted ME, Hiebert SW. The t(8;21) fusion product, AML-1-ETO, associates with C/EBP-alpha, inhibits C/EBP-alpha-dependent transcription, and blocks granulocytic differentiation. Mol Cell Biol. 1998;18(1):322–333.PubMedGoogle Scholar
  112. 112.
    Wiemels JL, Xiao Z, Buffler PA, et al. In utero origin of t(8;21) AML1-ETO translocations in childhood acute myeloid leukemia. Blood. 2002;99(10):3801–3805.PubMedCrossRefGoogle Scholar
  113. 113.
    Wiemels JL, Ford AM, Van Wering ER, Postma A, Greaves M. Protracted and variable latency of acute lymphoblastic leukemia after TEL-AML1 gene fusion in utero. Blood. 1999;94(3):1057–1062.PubMedGoogle Scholar
  114. 114.
    Yan M, Kanbe E, Peterson LF, et al. A previously unidentified alternatively spliced isoform of t(8;21) transcript promotes leukemogenesis. Nat Med. 2006;12(8):945–949.PubMedCrossRefGoogle Scholar
  115. 115.
    Yang G, Khalaf W, van de Locht L, et al. Transcriptional repression of the Neurofibromatosis-1 tumor suppressor by the t(8;21) fusion protein. Mol Cell Biol. 2005;25(14):5869–5879.PubMedCrossRefGoogle Scholar
  116. 116.
    Yang Y, Wang W, Cleaves R, et al. Acceleration of G(1) cooperates with core binding factor beta-smooth muscle myosin heavy chain to induce acute leukemia in mice. Cancer Res. 2002;62(8):2232–2235.PubMedGoogle Scholar
  117. 117.
    Yoshida N, Ogata T, Tanabe K, et al. Filamin A-bound PEBP2beta/CBFbeta is retained in the cytoplasm and prevented from functioning as a partner of the Runx1 transcription factor. Mol Cell Biol. 2005;25(3):1003–1012.PubMedCrossRefGoogle Scholar
  118. 118.
    Yuan Y, Zhou L, Miyamoto T, 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(18):10398–10403.PubMedCrossRefGoogle Scholar
  119. 119.
    Zhang DE, Hetherington CJ, Meyers S, et al. CCAAT enhancer-binding protein (C/EBP) and AML1 (CBF alpha2) synergistically activate the macrophage colony-stimulating factor receptor promoter. Mol Cell Biol. 1996;16(3):1231–1240.PubMedGoogle Scholar
  120. 120.
    Zhang DE, Fujioka K, Hetherington CJ, et al. Identification of a region which directs the monocytic activity of the colony-stimulating factor 1 (macrophage colony-stimulating factor) receptor promoter and binds PEBP2/CBF (AML1). Mol Cell Biol. 1994;14(12):8085–8095.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Division of Pediatric Hematology/OncologyDepartment of Pediatrics Monroe Carell Jr. Children’s Hospital at Vanderbilt and the Vanderbilt-Ingram Cancer CenterNashvilleUSA

Personalised recommendations