Screening microRNA-196 targets in 11q23-translocation acute myeloid leukemia reveal mechanisms maintaining leukemia stemness with therapeutic potential [RNA-seq]

microRNA are aberrantly expressed in acute myeloid leukemia (AML), and clinically may have diagnostic, prognostic, and therapeutic value. We identify one such microRNA, miR-196b, is essential for MLL-AF9 leukemia initiation and maintenance. To discover how miR-196b contributes to leukemogenesis, we utilized multiple unbiased approaches that identified and functionally screened miR-196b target activity in AML. Our studies resolved how conflicting networks of miRNA-regulated targets are integrated during leukemogenesis. This work uncovered two miR-196b direct targets, the cell cycle regulator Cdkn1b (p27Kip1) and Polycomb group member Phc2, that independently cooperate with MLL-AF9 to promote leukemogenesis by regulating stem cell transcriptional programs. Finally, we found that therapeutic disruption of miR-196b direct targeting of Cdkn1b suppresses leukemogenesis. Overall design: To identify the gene expression changes assoicated with knockdown of Cdkn1b and knockdown of Phc2 in murine MLL-AF9 leukemia cells.

10

Meyer SE, Muench DE, Rogers AM, Newkold TJ, Orr E, O'Brien E, Perentesis JP, Doench JG, Lal A, Morris PJ, Thomas CJ, Lieberman J, McGlinn E, Aronow BJ, Salomonis N, Grimes HL