Abstract
AML1/Evi-1 is a chimeric protein that is derived from t(3;21), found in blastic transformation of chronic myelogenous leukemia. It is composed of the N-terminal AML1 portion with the DNA-binding Runt domain and the C-terminal Evi-1 portion. It has been shown to dominantly repress AML1-induced transactivation. The mechanism for it has been mainly attributed to competition with AML1 for the DNA-binding and for the interaction with PEBP2β (CBFβ), a partner protein which heterodimerizes with AML1. It was recently found that Evi-1 interacts with C-terminal binding protein (CtBP) to repress TGFβ-induced transactivation. Here, we demonstrate that AML1/Evi-1 interacts with CtBP in SKH1 cells, a leukemic cell line which endogenously overexpresses AML1/Evi-1 and that AML1/Evi-1 requires the interaction with CtBP to repress AML1-induced transactivation. The association with CtBP is also required when AML1/Evi-1 blocks myeloid differentiation of 32Dcl3 cells induced by granulocyte colony-stimulating factor. Taken together, it is suggested that one of the mechanisms for AML1/Evi-1-associated leukemogenesis should be an aberrant recruitment of a corepressor complex by the chimeric protein.
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Acknowledgements
We thank M Ohki (National Cancer Center Research Institute, Tokyo, Japan) for providing AML1, Y Ito (Institute for Virus Research, Kyoto University, Japan) for PEBP2β, DE Zhang (The Scripps Research Institute, La Jolla, CA, USA) for pM-CSF-R-luc, SL McKnight (Johns Hopkins University, Baltimore, MD, USA) for C/EBPα, SL Schreiber (Harvard University, Cambridge, MA, USA) for Flag-HDAc1, G Chinnadurai (St. Louis University, MO, USA) for T7-hCtBP1, K Arai (The Institute of Medical Science, University of Tokyo, Japan) for pME18S, and J Miyazaki (Osaka University, Japan) for pCXN2. The murine IL-3 is a generous gift from Kirin Brewery (Tokyo, Japan). This study is supported in part by Grants-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare and from the ministry of Education, Culture, Sports, Science and Technology of Japan.
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Izutsu, K., Kurokawa, M., Imai, Y. et al. The t(3;21) fusion product, AML1/Evi-1 blocks AML1-induced transactivation by recruiting CtBP. Oncogene 21, 2695–2703 (2002). https://doi.org/10.1038/sj.onc.1205356
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DOI: https://doi.org/10.1038/sj.onc.1205356
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