Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Oncogenes, Fusion Genes and Tumor Suppressor Genes

Overexpression of an isoform of AML1 in acute leukemia and its potential role in leukemogenesis

Leukemia volume 23, pages 739–745 (2009)Cite this article

Abstract

AML1/RUNX1 is a critical transcription factor in hematopoietic cell differentiation and proliferation. From the AML1 gene, at least three isoforms, AML1a, AML1b and AML1c, are produced through alternative splicing. AML1a interferes with the function of AML1b/1c, which are often called AML1. In this study, we found a higher expression level of AML1a in acute lymphoblastic leukemia and acute myeloid leukemia (AML)-M2 patients in comparison to the controls. Additionally, AML1a represses transcription of promoter of macrophage colony-stimulating factor receptor mediated by AML1b, indicating that AML1a antagonized the effect of AML1b. To investigate the role of AML1a in hematopoiesis and leukemogenesis in vivo, murine bone marrow mononuclear cells were transduced with AML1a and then transplanted into lethally irradiated mice, which developed lymphoblastic leukemia after transplantation. Taken together, these results indicate that overexpression of AML1a may be an important contributing factor to leukemogenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Miyoshi H, Ohira M, Shimizu K, Mitani K, Hirai H, Imai T et al. Alternative splicing and genomic structure of the AML1 gene involved in acute myeloid leukemia. Nucleic Acids Res 1995; 23: 2762–2769.

    Article  CAS  PubMed Central  Google Scholar 

  2. 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, AMLl. Proc Natl Acad Sci USA 1991; 88: 10431–10434.

    Article  CAS  Google Scholar 

  3. Nucifora G, Birn DJ, Espinosa R, Erickson P, LeBeau MM, Roulston D et al. Involvement of the AML1 gene in therapy-related leukemia and in chronic myeloid leukemia in blast crisis. Blood 1993; 81: 2728–2734.

    CAS  Google Scholar 

  4. Golub TR, Barker GF, Bohlander SK, Hiebert SW, Ward DC, Bray-Ward P et al. Fusion of the Tel gene on 12p13 to the AML1 on 21q22 in acute lymphoblastic leukemia. Proc Natl Acad Sci USA 1995; 92: 4917–4921.

    Article  CAS  Google Scholar 

  5. Meyers S, Lenny N, Hiebert SW . The t (8; 21) fusion protein interferes with AML-1B-dependent transcnptional activation. Mol cell Biol 1995; 15: 1974–1982.

    Article  CAS  PubMed Central  Google Scholar 

  6. Tanaka T, Tanaka K, Ogawa S, Kurokawa M, Mitani K, Nishida J et al. An acute myeloid leukemia gene, AML1, regulates hemopoietic myeloid cell differentiation and transcriptional activation antagonistically by two alternative spliced forms. EMBO J 1995; 14: 341–350.

    Article  CAS  PubMed Central  Google Scholar 

  7. 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.

    Article  CAS  PubMed Central  Google Scholar 

  8. Wang Q, Stacy T, Binder M, Marín-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.

    Article  CAS  PubMed Central  Google Scholar 

  9. Ichikawa M, Asai T, Saito T, Seo S, Yamazaki I, Yamagata T et al. AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis. Nat Med 2004; 10: 299–304.

    Article  CAS  PubMed Central  Google Scholar 

  10. Kundu M, Compton S, Garrett-Beal L, Stacy T, Starost MF, Eckhaus M et al. Runx1 deficiency predisposes mice to T-lymphoblastic lymphoma. Blood 2005; 106: 3621–3624.

    Article  CAS  PubMed Central  Google Scholar 

  11. Uchida H, Zhang J, Nimer SD . AML1A and AML1B can transactivate the human IL-3 promoter. J Immunol 1997; 158: 2251–2258.

    CAS  Google Scholar 

  12. Britos-Bray M, Friedman AD . Core binding factor cannot synergistically activate the myeloperoxidase proximal enhancer in immature myeloid cells without c-Myb. Mol Cell Biol 1997; 17: 5127–5135.

    Article  CAS  PubMed Central  Google Scholar 

  13. Nuchprayoon I, Meyers S, Scott LM, Suzow J, Hiebert S, Friedman AD . PEBP2/CBF, the murine homolog of the human myeloid AML1 and PEBP2b/CBFb proto-oncoproteins, regulates the murine myeloperoxidase and neutrophil elastase genes in immature myeloid cells. Mol Cell Biol 1994; 14: 5558–5568.

    Article  CAS  PubMed Central  Google Scholar 

  14. Cockerill PN, Osborne CS, Bert AG, Grotto RJ . Regulation of GM-CSF gene transcription by core-binding factor. Cell Growth Differ 1996; 7: 917–922.

    CAS  PubMed  Google Scholar 

  15. Rhoades KL, Hetherington CJ, Rowley JD, Hiebert SW, Nucifora G, Tenen DG 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: 11895–11900.

    Article  CAS  PubMed Central  Google Scholar 

  16. Zhang DE, Hetherington CJ, Meyers S, Rhoades KL, Larson CJ, Chen HM 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: 1231–1240.

    Article  CAS  PubMed Central  Google Scholar 

  17. Fujii M, Hayashi K, Niki M, Chiba N, Meguro K, Endo K et al. Overexpression of AML1 renders a T hybridoma resistant to T cell receptor mediated apoptosis. Oncogene 1998; 17: 1813–1820.

    Article  CAS  Google Scholar 

  18. Daga A, Tighe JE, Calabi F . Leukaemia/Drosophila homology. Nature 1992; 356: 484.

    Article  CAS  Google Scholar 

  19. Kagoshima H, Shigesada K, Satake M, Ito Y, Miyoshi H, Ohki M et al. The runt domain identifies a new family of heteromeric transcriptional regulators. Trends Genet 1993; 9: 338–341.

    Article  CAS  Google Scholar 

  20. Meyers S, Downing JR, Hiebert SW . Identification of AML-1 and the (8;21) translocation protein (AML-1/ETO) as sequence specific DNA binding proteins: the runt homology domain is required for DNA binding and protein–protein interactions. Mol Cell Biol 1993; 13: 6336–6345.

    Article  CAS  PubMed Central  Google Scholar 

  21. 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.

    Article  CAS  PubMed Central  Google Scholar 

  22. Ogawa E, Inuzuka M, Maruyama M, Satake M, Naito-Fujimoto M, Ito Y et al. Molecular cloning and characterization of PEBP2b, the heterodimeric partner of a novel Drosophila runt-related DNA binding protein PEBP2. Virology 1993; 194: 314–331.

    Article  CAS  Google Scholar 

  23. 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: 2667–2674.

    CAS  PubMed  Google Scholar 

  24. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gealnick HR et al Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol 1976; 33: 451–458.

    Article  CAS  Google Scholar 

  25. Lo Coco F, Foa R . Diagnostic and prognostic advances in the immunophenotypic and genetic characterization of acute leukaemia. Eur J Haematol 1995; 55: 1–9.

    Article  CAS  Google Scholar 

  26. Zhang X, Diao S, Rao Q, Xing H, Liu H, Liao X et al. Identification of a novel isoform of iASPP and its interaction with p53. J Mol Biol 2007; 368: 1162–1171.

    Article  CAS  Google Scholar 

  27. Fenske TS, Pengue G, Mathews V, Hanson PT, Hamm SE, Riaz N et al. Stem cell expression of the AML1/ETO fusion protein induces a myeloproliferative disorder in mice. Proc Natl Acad Sci USA 2004; 101: 15184–15189.

    Article  CAS  Google Scholar 

  28. Ogawa E, Maruyama M, Kagoshima H, Inuzuka M, Lu J, Satake M 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.

    Article  CAS  Google Scholar 

  29. Bäsecke J, Feuring-Buske M, Brittinger G, Schaefer UW, Hiddemann W, Griesinger F . Transcription of AML1 in hematopoietic subfractions of normal adults. Ann Hematol 2002; 81: 254–257.

    Article  Google Scholar 

  30. Sato T, Ito R, Nunomura S, Ohno S, Hayashi K, Satake M et al. Requirement of transcription factor AML1 in proliferation of developing thymocytes. Immunol Lett 2003; 89: 39–46.

    Article  CAS  Google Scholar 

  31. Tsuzuki S, Hong D, Gupta R, Matsuo K, Seto M, Enver T . Isoform-specific potentiation of stem and progenitor cell engraftment by AML1/RUNX1. PLoS Med 2007; 4: e172.

    Article  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to Hongguang Ying (State Key Laboratory of Experimental Hematology, China) for histological analysis. We thank Prof Misao Ohki (Saitama Cancer Center Research Institute, Japan) and Dr Hiebert (St Jude Children's Hospital, USA) for providing pBlue-script II KS (+) plasmid containing AML1a cDNA and pCMV5-AML1b plasmid, respectively. This work was supported by Major State Basic Research Development Program (2006CB910406) and National Natural Science Fund (30871096) of China.

Author information

Author notes

  1. Q Zhang

    Present address: 4Current address: Guangdong No. 2 Provincial People’s Hospital, Guangzhou 510010, P.R. China.,

  2. X Liu and Q Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, P.R. China

    X Liu, Q Zhang, C Zhou, H Xing, Z Tian, Q Rao, M Wang & J Wang

  2. Department of pathology, University of California San Diego, La Jolla, CA, USA

    D-E Zhang

Authors
  1. X Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Q Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D-E Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Z Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Q Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Wang.

Additional information

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, X., Zhang, Q., Zhang, DE. et al. Overexpression of an isoform of AML1 in acute leukemia and its potential role in leukemogenesis. Leukemia 23, 739–745 (2009). https://doi.org/10.1038/leu.2008.350

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2008.350

Keywords

This article is cited by

Search

Advanced search

Quick links