International Journal of Hematology

, Volume 74, Issue 3, pp 252–257 | Cite as

RUNX1/AML1: A Central Player in Hematopoiesis

  • Tsukasa Okuda
  • Motohiro Nishimura
  • Mitsushige Nakao
  • Yasuko Fujitaa
Progress in hematology


It has been well established that a number of transcription factors play critical roles in regulating the fate of hematopoietic stem cell populations. One of them is the leukemia-associated transcription factor acute myeloid leukemia 1 (AML1; also known as runt-related transcription factor 1, or RUNX1). This gene was originally cloned from the breakpoint of the t(8;21) reciprocal chromosome translocation and was later recognized as one of the most frequent targets of leukemia-associated gene aberrations. Gene-targeting experiments revealed that transcriptionally active AML1 is essential for the establishment of definitive hematopoiesis. More specifically, this gene functions in the emergence of the hematopoietic progenitor cells from the hemogenic endothelium by budding in the aorta-gonad-mesonephros region, and its expression points to the sites with strong potential for the emergence of hematopoietic stem cells. This review discusses aspects of the biologic properties of AML1 in early hematopoietic development.

Key words

RUNX1 AML1 Hematopoiesis AGM region Hemogenic endothelium 


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  1. 1.
    Medvinsky A, Dzierzak E. Definitive hematopoiesis is autonomously initiated by the AGM region.Cell. 1996;86:897–906.CrossRefPubMedGoogle Scholar
  2. 2.
    Shivdasani RA, Orkin SH. The transcriptional control of hemato-poiesis.Blood. 1996;87:4025–4039.PubMedGoogle Scholar
  3. 3.
    Miyoshi H, Shimizu K, Kozu T, et al. 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;88:10431–10434.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Mitani K, Ogawa S, Tanaka T, et al. Generation of th.AML1-EVI-1 fusion gene in the t(3;21)(q26;q22) causes blastic crisis in chronic myelocytic leukemia.EMBO J. 1994;13:504–510.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Nucifora G, Begy CR, Kobayashi H, et al. Consistent intergenic splicing and production of multiple transcripts betwee.AML1 at 21q22 and unrelated genes at 3q26 in (3;21)(q26;q22) translocations.Proc Natl Acad Sci USA. 1994;91:4004–4008.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Romana SP, Mauchauffe M, Le Coniat M, et al. The t(12;21) of acute lymphoblastic leukemia results gene fusion.Blood. 1995;85:3662–3670.PubMedGoogle Scholar
  7. 7.
    Golub TR, Barker GF, Bohlander SK, et al. Fusion of the TEL gene on 12p13 to th.AML1 gene on 21q22 in acute lymphoblastic leukemia.Proc Natl Acad Sci USA. 1995;92:4917–4921.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    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;91:4028–4037.PubMedGoogle Scholar
  9. 9.
    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.CrossRefPubMedGoogle Scholar
  10. 10.
    Osato M, Asou N, Abdalla E, et al. Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2alphaB gene associated with myeloblastic leukemias.Blood. 1999;93:1817–1824.PubMedGoogle Scholar
  11. 11.
    Song WJ, Sullivan MG, Legare RD, et al. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia.Nat Genet. 1999;23:166–175.CrossRefPubMedGoogle Scholar
  12. 12.
    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;90:6859–6863.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    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;13:3324–3339.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kagoshima H, Shigesada K, Satake M, et al. The Runt domain identifies a new family of heteromeric transcriptional regulators.Trends Genet. 1993;9:338–341.CrossRefPubMedGoogle Scholar
  15. 15.
    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;4:1701–1713.CrossRefPubMedGoogle Scholar
  16. 16.
    Daga A, Karlovich CA, Dumstrei K, Banerjee U. Patterning of cells in the Drosophila eye by Lozenge, which shares homologous domains with AML1.Genes Dev. 1996;10:1194–1205.CrossRefPubMedGoogle Scholar
  17. 17.
    Lebestky T, Chang T, Hartenstein V, Banerjee U. Specification of Drosophila hematopoietic lineage by conserved transcription factors.Science. 2000;288:146–149.CrossRefPubMedGoogle Scholar
  18. 18.
    Ito Y. Molecular basis of tissue-specific gene expression mediated by the runt domain transcription factor PEBP2/CBF.Genes Cells. 1999;4:685–696.CrossRefPubMedGoogle Scholar
  19. 19.
    Speck NA, Terryl S. A new transcription factor family associated with human leukemias.Crit Rev Eukaryot Gene Expr. 1995;5:337–364.CrossRefPubMedGoogle Scholar
  20. 20.
    Kanno T, Kanno Y, Chen LF, Ogawa E, Kim WY, Ito Y. Intrinsic transcriptional activation-inhibition domains of the polyomavirus enhancer binding protein 2/core binding factor alpha subunit revealed in the presence of the beta subunit.Mol Cell Biol. 1998;18:2444–2454.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    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;95:11590–11595.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Imai Y, Kurokawa M, Tanaka K, et al. TLE, the human homolog of groucho, interacts with AML1 and acts as a repressor of AML1-induced transactivation.Biochem Biophys Res Commun. 1998;252:582–589.CrossRefPubMedGoogle Scholar
  23. 23.
    Jimenez G, Pinchin SM, Ish-Horowicz D. In vivo interactions of the Drosophila Hairy and Runt transcriptional repressors with target promoters.EMBO J. 1996;15:7088–7098.PubMedPubMedCentralGoogle Scholar
  24. 24.
    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;275:651–656.CrossRefPubMedGoogle Scholar
  25. 25.
    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;84:321–330.CrossRefPubMedGoogle Scholar
  26. 26.
    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;93:3444–3449.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Wang Q, Stacy T, Miller JD, et al. The CBFbeta subunit is essential for CBFalpha2 (AML1) function in vivo.Cell. 1996;87:697–708.CrossRefPubMedGoogle Scholar
  28. 28.
    Sasaki K, Yagi H, Bronson RT, et al. Absence of fetal liver hematopoiesis in mice deficient in transcriptional coactivator core binding factor beta.Proc Natl Acad Sci USA. 1996;93:12359–12363.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Niki M, Okada H, Takano H, et al. Hematopoiesis in the fetal liver is impaired by targeted mutagenesis of a gene encoding a non-DNA binding subunit of the transcription factor, polyomavirus enhancer binding protein 2/core binding factor.Proc Natl Acad Sci USA. 1997;94:5697–702.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    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;20:723–733.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Okuda T, Takeda K, Fujita Y, et al. Biological characteristics of the leukemia-associated transcriptional factor AML1 disclosed by hematopoietic rescue o.AML1-deficient embryonic stem cells by using a knock-in strategy.Mol Cell Biol. 2000;20:319–28.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Shivdasani RA, Rosenblatt MF, Zucker-Franklin D, et al. Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MGDF in megakaryocyte development.Cell. 1995;81:695–704.CrossRefPubMedGoogle Scholar
  33. 33.
    Takakura N, Watanabe T, Suenobu S, et al. A role for hematopoietic stem cells in promoting angiogenesis.Cell. 2000;102:199–209.CrossRefPubMedGoogle Scholar
  34. 34.
    Mukouyama Y, Chiba N, Hara T, et al. The AML1 transcription factor functions to develop and maintain hematogenic precursor cells in the embryonic aorta-gonad-mesonephros region.Dev Biol. 2000;220:27–36.CrossRefPubMedGoogle Scholar
  35. 35.
    Satake M, Nomura S, Yamaguchi-Iwai Y, et al. Expression of the Runt domain-encoding PEBP2 alpha genes in T cells during thymic development. Mol Cell. Biol. 1995;15:1662–1670.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Simeone A, Daga A, Calabi F. Expression of runt in the mouse embryo.Dev Dyn. 1995;203:61–70.CrossRefPubMedGoogle Scholar
  37. 37.
    North T, Gu TL, Stacy T, et al. Cbfa2 is required for the formation of intra-aortic hematopoietic clusters.Development. 1999;126:2563–2575.PubMedGoogle Scholar
  38. 38.
    Garcia-Porrero JA, Godin IE, Dieterlen-Lievre F. Potential intraembryonic hemogenic sites at pre-liver stages in the mouse.Anat Embryol (Berl). 1995;192:425–435.CrossRefPubMedGoogle Scholar
  39. 39.
    Wood HB, May G, Healy L, Enver T, Morriss-Kay GM. CD34 expression patterns during early mouse development are related to modes of blood vessel formation and reveal additional sites of hematopoiesis.Blood. 1997;90:2300–2311.PubMedGoogle Scholar
  40. 40.
    Jaffredo T, Gautier R, Eichmann A, Dieterlen-Lievre F. Intraaortic hemopoietic cells are derived from endothelial cells during ontogeny.Development. 1998;125:4575–4583.PubMedGoogle Scholar
  41. 41.
    Nishikawa SI, Nishikawa S, Kawamoto H, et al. In vitro generation of lymphohematopoietic cells from endothelial cells purified from murine embryos.Immunity. 1998;8:761–769.CrossRefPubMedGoogle Scholar
  42. 42.
    Yokomizo T, Ogawa M, Osato M, et al. Requirement of Runx1/AML1/PEBP2alphaB for the generation of haematopoietic cells from endothelial cells.Genes Cells. 2001;6:13–23.CrossRefPubMedGoogle Scholar
  43. 43.
    Dzierzak E, Medvinsky A. Mouse embryonic hematopoiesis.Trends Genet. 1995;11:359–366.CrossRefPubMedGoogle Scholar
  44. 44.
    de Bruijn MF, Speck NA, Peeters MC, Dzierzak E. Definitive hematopoietic stem cells first develop within the major arterial regions of the mouse embryo.EMBO J. 2000;59:2465–2474.CrossRefGoogle Scholar
  45. 45.
    Cai Z, de Bruijn M, Ma X, Dortland B, Luteijn T, Downing JR, Dzierzak E. Haploinsufficiency of AML1 affects the temporal and spatial generation of hematopoietic stem cells in the mouse embryo.Immunity. 2000;13:423–231.CrossRefPubMedGoogle Scholar
  46. 46.
    Telfer JC, Rotherberg EV. Expression and function of a stem cell promoter for the murine CBFalpha2 gene: distinct roles and regulation in natural killer and T cell development.Dev Biol. 2001;229:363–382.CrossRefPubMedGoogle Scholar
  47. 47.
    Fujita Y, Nishimura M, Taniwaki M, Abe T, Okuda T. Identification of an alternatively spliced form of the mouse AML1/RUNX1 gene transcript AML1c and its expression in early hematopoietic development.Biochem Biophys Res Commun. 2001;281:1248–1255.CrossRefPubMedGoogle Scholar
  48. 48.
    Ghozi MC, Bernstein Y, Negreanu V, Levanon D, Groner Y. Expression of the human acute myeloid leukemia gene AML1 is regulated by two promoter regions.Proc Natl Acad Sci USA. 1996;93:1935–1940.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2001

Authors and Affiliations

  • Tsukasa Okuda
    • 1
  • Motohiro Nishimura
    • 1
    • 2
  • Mitsushige Nakao
    • 1
    • 3
  • Yasuko Fujitaa
    • 1
    • 3
  1. 1.Departments of HygieneKyoto Prefectural University of MedicineKyotoJapan
  2. 2.Departments of Thoracic SurgeryKyoto Prefectural University of MedicineKyotoJapan
  3. 3.Departments of Internal MedicineKyoto Prefectural University of MedicineKyotoJapan

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