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

Year: 2018
Type: article
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: Sara E. Meyer, David E. Muench, Andrew M. Rogers, Tess J. Newkold, Emily Orr, Eric O’Brien, 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
Institutions: Cincinnati Children's Hospital Medical Center, Broad Institute, National Institutes of Health, National Cancer Institute, National Center for Advancing Translational Sciences, Boston Children's Hospital, Harvard University, Australian Regenerative Medicine Institute, EMBL Australia, Monash University
Language: English
Subfield: Hematology
Field: Medicine
Open Access status: hybrid
Funders: Leukemia and Lymphoma Society, Ladies Auxiliary to the Veterans of Foreign Wars, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Center for Clinical and Translational Science, University of Illinois at Chicago, Australian Government, CancerFree KIDS, State Government of Victoria, National Institutes of Health, Sidney Kimmel Comprehensive Cancer Center, National Cancer Institute, National Institute of Environmental Health Sciences
Awards: G1801458859, G2731978795, G2766465774, G4240366744, G4439132751, G820931977, G9000073351, G9000170100, G9000218274, G9000296867
OpenAlex ID: W2822170633
FWCI: 1.672
Cites: 121
Cited by: 31
Related to: 10