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Acute Leukemias

EVI-1 interacts with histone methyltransferases SUV39H1 and G9a for transcriptional repression and bone marrow immortalization

Leukemia volume 24, pages 81–88 (2010)Cite this article

Abstract

The ecotropic viral integration site-1 (EVI-1) is a nuclear transcription factor and has an essential function in the proliferation/maintenance of haematopoietic stem cells. Aberrant expression of EVI-1 has been frequently found in myeloid leukaemia as well as in several solid tumours, and is associated with a poor patient survival. It was recently shown that EVI-1 associates with two different histone methyltransferases (HMTs), SUV39H1 and G9a. However, the functional roles of these HMTs in EVI-1-mediated leukemogenesis remain unclear. In this study, we showed that EVI-1 physically interacts with SUV39H1 and G9a, but not with Set9. Immunofluorescence analysis revealed that EVI-1 colocalizes with these HMTs in nuclei. We also found that the catalytically inactive form of SUV39H1 abrogates the transcriptional repression mediated by EVI-1, suggesting that SUV39H1 is actively involved in EVI-1-mediated transcriptional repression. Furthermore, RNAi-based knockdown of SUV39H1 or G9a in Evi-1-expressing progenitors significantly reduced their colony-forming activity. In contrast, knockdown of these HMTs did not impair bone marrow immortalization by E2A/HLF. These results indicate that EVI-1 forms higher-order complexes with HMTs, and this association has a role in the transcription repression and bone marrow immortalization. Targeting these HMTs may be of therapeutic benefit in the treatment for EVI-1-related haematological malignancies.

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Acknowledgements

We thank T Kitamura for Plat-E packaging cells, H Nakauchi and M Onodera for pGCDNsam-eGFP retroviral vector, T Inaba, M Tachibana, Y Shinkai, K Wright and D Reinberg for cDNAs (see Materials and methods), Y Shimamura for expert technical assistance, and KYOWA KIRIN for cytokines. This work was supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, and by Health and Labour Sciences Research grants from the Ministry of Health, Labour and Welfare.

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Authors and Affiliations

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

    S Goyama, E Nitta, T Yoshino, S Kako, N Watanabe-Okochi, M Shimabe, Y Imai & M Kurokawa

  2. Department of Transfusion Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan

    S Goyama & K Takahashi

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  1. S Goyama
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Correspondence to M Kurokawa.

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

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Goyama, S., Nitta, E., Yoshino, T. et al. EVI-1 interacts with histone methyltransferases SUV39H1 and G9a for transcriptional repression and bone marrow immortalization. Leukemia 24, 81–88 (2010). https://doi.org/10.1038/leu.2009.202

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