Document Type
Article
Publication Date
9-1-2018
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.
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
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.