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Oncogenes, Fusion Genes and Tumor Suppressor Genes

AML1-Evi-1 specifically transforms hematopoietic stem cells through fusion of the entire Evi-1 sequence to AML1

Leukemia volume 22, pages 1241–1249 (2008)Cite this article

Abstract

The t(3;21) chromosomal translocation seen in blastic crisis of chronic myeloid leukemia and secondary leukemias results in a formation of a chimeric protein AML1-Evi-1, which suppresses wild-type AML1 function. Loss of AML1 function causes expansion of hematopoietic progenitor cells, whereas it is not sufficient for the development of leukemia. To identify essential mechanisms through which AML1-Evi-1 exerts full leukemogenic potential, we introduced AML1-Evi-1 and its mutants in murine bone marrow cells, and evaluated their transforming activities by colony replating assays. The transforming activity of AML1-Evi-1 was lost when any of the known functional domains of Evi-1 was deleted from the chimeric protein, and forced expression of Evi-1 did not transform the AML1-deleted bone marrow cells. Unlike the MLL-ENL and AML1-ETO leukemia-related chimeric proteins, AML1-Evi-1 could transform only the hematopoietic stem cell fraction. Moreover, AML1-Evi-1-transformed cells show a cell-marker profile distinct from that of the cells transformed by AML1-ETO, which also suppresses AML1 function. Thus, leukemogenic activity of AML1-Evi-1 may be due to activation of molecular mechanisms distinct from those activated by MLL-ENL or AML1-ETO in the hematopoietic stem cell fractions.

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Acknowledgements

We thank SW Hiebert for AML1-ETO cDNA, T Kitamura for MLL-ENL cDNA, R Kühn and J Takeda for Mx-cre transgenic mice, Kirin Brewery for thrombopoietin and Y Sawamoto and Y Shimamura for excellent technical assistance. This work was supported in part by the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Grant-in-Aid for Scientific Research on Priority Areas, KAKENHI(18013014); Japan Society for the Promotion of Science(JSPS), Grant-in-Aid for JSPS Fellows (17-10666) and the Ministry of Health, Labour and Welfare, Health and Labour Sciences Research Grants.

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  1. M Takeshita and M Ichikawa: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    M Takeshita, M Ichikawa, E Nitta, S Goyama, T Asai, S Ogawa & M Kurokawa

  2. Department of Cell Therapy and Transplantation Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    S Chiba

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  1. M Takeshita
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  2. M Ichikawa
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Correspondence to M Kurokawa.

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Takeshita, M., Ichikawa, M., Nitta, E. et al. AML1-Evi-1 specifically transforms hematopoietic stem cells through fusion of the entire Evi-1 sequence to AML1. Leukemia 22, 1241–1249 (2008). https://doi.org/10.1038/leu.2008.53

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