miR-196b target screen reveals mechanisms maintaining leukemia stemness with therapeutic potential.

Paradigms and Technologies
Therapeutic Approaches

Abstract

We have shown that antagomiR inhibition of miRNA miR-21 and miR-196b activity is sufficient to ablate MLL-AF9 leukemia stem cells (LSC) in vivo. Here, we used an shRNA screening approach to mimic miRNA activity on experimentally verified miR-196b targets to identify functionally important and therapeutically relevant pathways downstream of oncogenic miRNA in MLL-r AML. We found Cdkn1b (p27Kip1) is a direct miR-196b target whose repression enhanced an embryonic stem cell-like signature associated with decreased leukemia latency and increased numbers of leukemia stem cells in vivo. Conversely, elevation of p27Kip1 significantly reduced MLL-r leukemia self-renewal, promoted monocytic differentiation of leukemic blasts, and induced cell death. Antagonism of miR-196b activity or pharmacologic inhibition of the Cks1-Skp2-containing SCF E3-ubiquitin ligase complex increased p27Kip1 and inhibited human AML growth. This work illustrates that understanding oncogenic miRNA target pathways can identify actionable targets in leukemia.

Authors

Meyer, Sara E; Muench, David E; Rogers, Andrew M; Newkold, Tess J; Orr, Emily; O'Brien, Eric; Perentesis, John P; Doench, John G; Lal, Ashish; Morris, Patrick; Thomas, Craig; Lieberman, Judy; McGlinn, Edwina; Aronow, Bruce J; Salomonis, Nathan; Grimes, H Leighton;

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