Overexpression And Knockout Of Mir-126 Both Promote Leukemogenesis Through Targeting Distinct Gene Signaling

It9s generally assumed that gain- and loss-of-function manipulations of a functionally important gene should lead to the opposite phenotypes. Surprisingly, here we show that both overexpression and knockout of miR-126 result in enhanced leukemogenesis in cooperation with t(8;21) fusion genes, AML1-ETO/RUNX1-RUNX1T1 or AML1-ETO9a (a potent oncogenic isoform of AML1-ETO). In accordance with our observation that increased expression of miR-126 is associated with unfavorable survival in patients with t(8;21) acute myeloid leukemia (AML), we show that miR-126 overexpression exhibits a stronger effect on long-term survival and progression of AML1-ETO9a-mediated leukemia stem/initiating cells (LSCs/LICs) in mice than does miR-126 knockout. Furthermore, miR-126 knockout substantially enhances responsiveness of leukemia cells to standard chemotherapy. Mechanistically, miR-126 overexpression activates genes that are highly expressed in LSCs/LICs and/or primitive hematopoietic stem/progenitor cells likely through targeting ERRFI1 and SPRED1, whereas miR-126 knockout activates genes that are highly expressed in committed, more differentiated hematopoietic progenitor cells presumably through inducing FZD7 expression. Our data demonstrate that miR-126 plays a critical but two-faceted role in leukemia, and thereby uncover a new layer of miRNA regulation in cancer. Moreover, as miR-126 depletion can sensitize AML cells to standard chemotherapy, our data also suggest that miR-126 represents a promising therapeutic target.