A regulatory circuitry between miR-193a/miR-600 and WT1 enhances leukemogenesis in acute myeloid leukemia

The aberrant overexpression of Wilms tumor-1 (WT1) in acute myeloid leukemia (AML) plays an important role in blast cell survival by enhancing proliferation and inhibiting apoptosis. However, the mechanism underlying the overexpression of WT1 remains unclear. Here, we identified miR-193a (miR-193a-5p) and miR-600 targeting and degrading WT1. MiR-193a and miR-600 synergistically reduced WT1 expression and suppressed the activity of a luciferase reporter by binding coding sequence and the 3'-untranslated region of WT1 mRNA, respectively. Furthermore, the expression of miR-193a and miR-600 was decreased in AML patients compared with normal controls. DNA hypermethylation in pre-miR-193a promoter, but not pre-miR-600 promoter, caused the downregulation of miR-193a. Most intriguingly, ectopic expression of WT1 inhibited miR-600 expression, in turn, by binding the putative pre-miR-600 promoter, leading to the downregulation of miR-600 in AML blasts. Ectopic expression of miR-193a and miR-600 synergistically inhibited cell proliferation, induced apoptosis, and decreased colony formation in leukemia cells. Finally, overexpression of miR-193a and miR-600 decreased the growth of K562-inoculated tumor xenografts and extended survival time in THP1-transplanted leukemia mice. In conclusion, these data reveal an important role of miRNAs-WT1 circuitry in leukemia cells and the therapeutic promise of restoring miR-193a and miR-600 expression in AML patients.