Identification of microRNAs regulating apoptosis and elucidation of their roles in tumorigenesis

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The Wilms’ tumor gene WT1 is overexpressed and plays an oncogenic role in themajority of human leukemia and various types of solid tumors. Therefore, it is important to identify the molecular mechanism by which WT1 is overexpressed to understand their roles in tumorigenesis. In the present study, we identified microRNA-A (miR-A) as a miRNA that repressed WT1 expression by its binding to the WT1-3’UTR. miR-A-deficient mice exhibited high expression of WT1 in hematopoietic stem/progenitor cells (HSPCs) and developed myeloproliferative disorders (MPDs) characterized by expansion of myeloid cells in the BM, spleen and peripheral blood. Furthermore, silencing of WT1 expression in HSPCs of MPD miR-A-deficient mice by short hairpin RNA inhibited myeloid proliferation and differentiation in vitro. These results indicate that loss or decreased expression of miR-A plays an important role in the development of MPD through dysregulated overexpression of WT1 in HSPCs.