Title

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

Authors

Sara E. Meyer, Thomas Jefferson University; Cincinnati Children’s Hospital Medical CenterFollow
David E. Muench, Cincinnati Children’s Hospital Medical Center
Andrew M. Rogers, Cincinnati Children’s Hospital Medical Center
Tess J. Newkold, Cincinnati Children’s Hospital Medical Center
Emily Orr, Cincinnati Children’s Hospital Medical Center
Eric O'Brien, Cincinnati Children’s Hospital Medical Center
John P. Perentesis, Cincinnati Children’s Hospital Medical Center
John G. Doench, Broad Institute of MIT and Harvard
Ashish Lal, National Institutes of Health
Patrick J. Morris, National Institutes of Health
Craig J. Thomas, National Institutes of Health
Judy Lieberman, Boston Children's Hospital; Harvard Medical School
Edwina McGlinn, Monash University
Bruce J. Aronow, Cincinnati Children’s Hospital Medical Center
Nathan Salomonis, Cincinnati Children’s Hospital Medical Center
H. Leighton Grimes, Cincinnati Children’s Hospital Medical Center

Document Type

Article

Publication Date

9-1-2018

Comments

This article has been peer reviewed. It is the author’s final published version in Journal of Experimental Medicine, Volume 215, Issue 8, September 2018, Pages 2115-2136.

The published version is available at https://doi.org/10.1084/jem.20171312. Copyright © Meyer et al.

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 (p27^Kip1) 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^Kip1 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^Kip1 and inhibited human AML growth. This work illustrates that understanding oncogenic miRNA target pathways can identify actionable targets in leukemia.

Recommended Citation

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 J.; Thomas, Craig J.; Lieberman, Judy; McGlinn, Edwina; Aronow, Bruce J.; Salomonis, Nathan; and Grimes, H. Leighton, "miR-196b target screen reveals mechanisms maintaining leukemia stemness with therapeutic potential." (2018). Department of Cancer Biology Faculty Papers. Paper 139.
https://jdc.jefferson.edu/cbfp/139

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

PubMed ID

29997117

Language

English