MiR-196b Target Screen Reveals Mechanisms Maintaining Leukemia Stemness with Therapeutic Potential

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2018 Jul 13

PMID 29997117

Citations 17

Authors

Sara E Meyer

David E Muench

Andrew M Rogers

Tess J Newkold

Emily Orr

Eric OBrien

John P Perentesis

John G Doench

Ashish Lal

Patrick J Morris

Craig J Thomas

Judy Lieberman

Edwina McGlinn

Bruce J Aronow

Nathan Salomonis

H Leighton Grimes

Affiliations

Soon will be listed here.

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 (p27) 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 p27 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 p27 and inhibited human AML growth. This work illustrates that understanding oncogenic miRNA target pathways can identify actionable targets in leukemia.

Citing Articles

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miR-196b-Oct1/2 axis regulates DNMT3A-mutant AML pathogenesis.

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Signaling pathways governing the behaviors of leukemia stem cells.

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