Abstract
MEF2D fusion genes are newly discovered recurrent gene abnormalities that are detected in approximately 5% of acute lymphoblastic leukemia cases. We previously demonstrated that the vector-driven expression of MEF2D fusion proteins was markedly stronger than that of wild-type MEF2D; however, the underlying mechanisms and significance of this expression have yet to be clarified. We herein showed that the strong expression of MEF2D fusion proteins was caused by the loss of the target site of miRNA due to gene translocation. We identified the target region of miRNA located in the coding region and selected miR-122 as a candidate of the responsible miRNA. Mutations at a putative binding site of miR-122 increased MEF2D expression, while the transfection of its miRNA mimic reduced the expression of wild-type MEF2D, but not MEF2D fusion proteins. We also found that MEF2D fusion proteins inhibited the transcriptional activity of PAX5, a B-cell differentiation regulator in a manner that depended on fusion-specific strong expression and an association with histone deacetylase 4, which may lead to the differentiation disorders of B cells. Our results provide novel insights into the mechanisms underlying leukemia development by MEF2D fusion genes and the involvement of the deregulation of miRNA-mediated repression in cancer development.
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Acknowledgements
We are very grateful to Yoko Matsuyama and Chika Wakamatsu for their technical assistance. We would thank to Yukie Konishi, Manami Kira, Rie Kojima, Yuko Kojima, Youko Okada, and Saori Kanamori for their secretarial assistance. This study was supported in part by grants for Practical Research for Innovative Cancer Control (to FH, HM, and HK), for Programs for Development of Innovative Research on Cancer Therapeutics (P-DIRECT) (to TN), for Project for Cancer Research And Therapeutic Evolution (P-CREATE) (to TY), and for Leading Advanced Projects for Medical Innovation (LEAP) (to HM) from the Japan Agency for Medical Research and Development. This work was also supported by JSPS KAKENHI (to FH, TY, and HK).
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HK received research funding from Chugai Pharmaceutical Co., Ltd., Bristol-Myers Squibb, Kyowa-Hakko Kirin Co., Ltd., Zenyaku Kogyo Co., Ltd., FUJIFILM Corporation, Nippon Boehringer Ingelheim Co., Ltd., Astellas Pharma Inc., and Celgene Corporation, consulting fees from Astellas Pharma Inc. and Daiichi Sankyo Co., Ltd., and honoraria from Bristol-Myers Squibb and Pfizer Japan Inc. The remaining authors declare that they have no conflict of interest.
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Hirano, D., Hayakawa, F., Yasuda, T. et al. Chromosomal translocation-mediated evasion from miRNA induces strong MEF2D fusion protein expression, causing inhibition of PAX5 transcriptional activity. Oncogene 38, 2263–2274 (2019). https://doi.org/10.1038/s41388-018-0573-9
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DOI: https://doi.org/10.1038/s41388-018-0573-9
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