Chromosomal translocation-mediated evasion from miRNA induces strong MEF2D fusion protein expression, causing inhibition of PAX5 transcriptional activity

摘要

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.