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.

  • Review
  • Published:

Molecular mechanisms of leukemogenesis by AML1/EVI-1

Oncogene volume 23, pages 4263–4269 (2004)Cite this article

Abstract

The AML1/EVI-1 chimeric gene is generated by the t(3;21)(q26;q22) translocation and plays a pivotal role in progression of hematopoietic stem cell malignancies such as chronic myelocytic leukemia and myelodysplastic syndrome. In AML1/EVI-1, an N-terminal half of AML1 including a runt homology domain is fused to the entire zinc-finger EVI-1 protein. AML1 is essential for hematopoietic cell development in fetal liver and its lineage-specific differentiation in adult. In contrast, EVI-1 is barely expressed in normal hematopoietic cells, but it is overexpressed in chronic myelocytic leukemia in blastic crisis and myelodysplastic syndrome-derived leukemia. There are at least four mechanisms identified in AML1/EVI-1 fusion protein that possibly lead into malignant transformation of hematopoietic stem cells. Firstly, AML1/EVI-1 exerts dominant-negative effects over AML1-induced transcriptional activation. Although target genes repressed by AML1/EVI-1 are still not known, binding competition to a specific DNA sequence and histone deacetylase recruitment through a co-repressor CtBP in EVI-1 part are conceivable underlying mechanisms for the dominant-negative effects. Secondly, AML1/EVI-1 interferes with TGFβ signaling and antagonizes the growth-inhibitory effects of TGFβ. The first zinc-finger domain of EVI-1 associates with Smad3, a TGFβ signal transducer, and represses its transcriptional activity by recruiting histone deacetylase through CtBP that interacts with EVI-1. Thirdly, AML1/EVI-1 blocks JNK activity and prevents stress-induced apoptosis. AML1/EVI-1 associates with JNK through the first zinc-finger domain of EVI-1 and disturbs the association between JNK and its substrates. Lastly, AML1/EVI-1 enhances AP-1 activity by activating the c-Fos promoter depending on the second zinc-finger domain of EVI-1, and promotes cell proliferation. All these functions cooperatively contribute to the malignant transformation of the hematopoietic stem cells by AML1/EVI-1.

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
Figure 6

Similar content being viewed by others

References

  • Bae SC, Yamaguchi-Iwai Y, Ogawa E, Maruyama M, Inuzuka M, Kagoshima H, Shigesada K, Satake M and Ito Y . (1993). Oncogene, 8, 809–814.

  • Daga A, Tighe JE and Calabi F . (1992). Nature, 356, 484.

  • Huang G, Shigesada K, Ito K, Wee H-J, Yokomozo T and Ito Y . (2001). EMBO J., 20, 723–733.

  • Izutsu K, Kurokawa M, Imai Y, Ichikawa M, Asai T, Maki K, Mitani K and Hirai H . (2002). Oncogene, 21, 2695–2703.

  • Izutsu K, Kurokawa M, Imai Y, Maki K, Mitani K and Hirai H . (2001). Blood, 97, 2815–2822.

  • Kitabayashi I, Yokoyama A, Shimizu K and Ohki M . (1998). EMBO J., 17, 2994–3004.

  • Kurokawa M, Mitani K, Imai Y, Ogawa S, Yazaki Y and Hirai H . (1998a). Blood, 92, 4003–4012.

  • Kurokawa M, Mitani K, Irie K, Matsuyama T, Takahashi T, Chiba S, Yazaki Y, Matsumoto K and Hirai H . (1998b). Nature, 394, 92–94.

  • Kurokawa M, Mitani K, Yamagata T, Takahashi T, Izutsu K, Ogawa S, Moriguchi T, Nishida E, Yazaki Y and Hirai H . (2000). EMBO J., 19, 2958–2968.

  • Kurokawa M, Ogawa S, Tanaka T, Mitani K, Yazaki Y, Witte ON and Hirai H . (1995). Oncogene, 11, 833–840.

  • Mitani K, Ogawa S, Tanaka T, Kurokawa M, Yazaki Y and Hirai H . (1995). Br. J. Haematol., 90, 711–714.

  • Mitani K, Ogawa S, Tanaka T, Miyoshi H, Kurokawa M, Mano H, Yazaki Y, Misao O and Hirai H . (1994). EMBO J., 13, 504–510.

  • Miyoshi H, Shimizu K, Kozu T, Maseki N, Kaneko Y and Ohki M . (1991). Proc. Natl. Acad. Sci. USA, 88, 10431–10434.

  • Morishita K, Parganas E, Douglass EC and Ihle JN . (1990). Oncogene, 5, 963–971.

  • Morishita K, Parganas E, Willman CL, Whittaker MH, Drabkin H, Oval J, Taetle R, Valentine MB and Ihle JN . (1992). Proc. Natl. Acad. Sci. USA, 89, 3937–3941.

  • Morishita K, Parker DS, Mucenski ML, Jenkins NA, Copeland NG and Ihle JN . (1988). Cell, 54, 831–840.

  • Ogawa E, Inuzuka M, Maruyama M, Satake M, Naito-Fujimoto M, Ito Y and Shigesada K . (1993a). Virology, 194, 314–331.

  • Ogawa E, Maruyama M, Kagoshima H, Inuzuka M, Lu J, Satake M, Shigesada K and Ito Y . (1993b). Proc. Natl. Acad. Sci. USA, 90, 6859–6863.

  • Ogawa S, Kurokawa M, Tanaka T, Tanaka K, Hangaishi A, Mitani K, Kamada N, Yazaki Y and Hirai H . (1996a). Leukemia, 10, 788–794.

  • Ogawa S, Kurokawa M, Tanaka T, Mitani K, Inazawa J, Hanagaishi A, Tanaka K, Matsuo Y, Minowada J, Tsubota T, Yazaki Y and Hirai H . (1996b). Oncogene, 13, 183–191.

  • Okuda T, van Deursen J, Hiebert SW, Grosveld G and Downing JR . (1996). Cell, 84, 321–330.

  • Sasaki K, Yagi H, Bronson RT, Tomonaga K, Matsunashi T, Deguchi K, Tani Y, Kishimoto T and Komori T . (1996). Proc. Natl. Acad. Sci. USA, 93, 12359–12363.

  • Tanaka K, Tanaka T, Kurokawa M, Imai Y, Ogawa S, Mitani K, Yazaki Y and Hirai H . (1998). Blood, 91, 1688–1699.

  • Tanaka T, Mitani K, Kurokawa M, Ogawa S, Tanaka K, Nishida J, Yazaki Y, Shibata Y and Hirai H . (1995). Mol. Cell. Biol., 15, 2383–2392.

  • Tanaka T, Nishida J, Mitani K, Ogawa S, Yazaki Y and Hirai H . (1994). J. Biol. Chem., 269, 24020–24026.

  • Taniuchi I, Osato M, Egawa T, Sunshine MJ, Bae S-C, Komori T, Ito Y and Littman D . (2002). Cell, 111, 621–633.

  • Wang Q, Stacy T, Binder M, Marin-Padilla M, Sharpe AH and Speck NA . (1996a). Proc. Natl. Acad. Sci. USA, 93, 3444–3449.

  • Wang Q, Stacy T, Miller JD, Lewis AF, Gu TL, Huang X, Bushweller JH, Borie JC, Bories JC, Alt EW, Ryan G, Liu PP, Wynsaw-Boris A, Binder M, Marin-Padilla M, Sharpe AH and Speck NA . (1996b). Cell, 87, 697–708.

Download references

Author information

Authors and Affiliations

  1. Department of Hematology, Dokkyo University School of Medicine, 321-0293, Tochigi, Japan

    Kinuko Mitani

Authors
  1. Kinuko Mitani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kinuko Mitani.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mitani, K. Molecular mechanisms of leukemogenesis by AML1/EVI-1. Oncogene 23, 4263–4269 (2004). https://doi.org/10.1038/sj.onc.1207777

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207777

Keywords

This article is cited by

Search

Advanced search

Quick links