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
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
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.
Author information
Authors and Affiliations
Corresponding author
Rights 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
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1207777
Keywords
This article is cited by
-
Acute lymphoblastic leukemia-derived exosome inhibits cytotoxicity of natural killer cells by TGF-β signaling pathway
3 Biotech (2021)
-
Functional features of EVI1 and EVI1Δ324 isoforms of MECOM gene in genome-wide transcription regulation and oncogenicity
Oncogene (2016)
-
RUNX1-Evi-1 fusion gene inhibited differentiation and apoptosis in myelopoiesis: an in vivo study
BMC Cancer (2015)
-
The role of Smad signaling in hematopoiesis and translational hematology
Leukemia (2011)
-
Sumoylation of MEL1S at lysine 568 and its interaction with CtBP facilitates its repressor activity and the blockade of G-CSF-induced myeloid differentiation
Oncogene (2011)