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J Exp Med. 2018 Aug 6;215(8):2115-2136. doi: 10.1084/jem.20171312. Epub 2018 Jul 11.

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

Author information

1
Division of Immunobiology and Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
2
Division of Oncology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
3
Broad Institute of MIT and Harvard, Cambridge, MA.
4
Regulatory RNAs and Cancer Section, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
5
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD.
6
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA.
7
Department of Pediatrics, Harvard Medical School, Boston, MA.
8
EMBL Australia, Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.
9
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
10
Division of Immunobiology and Center for Systems Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH lee.grimes@cchmc.org.
11
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

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.

PMID:
29997117
PMCID:
PMC6080909
DOI:
10.1084/jem.20171312
[Indexed for MEDLINE]
Free PMC Article

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