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

The Journal of Experimental Medicine
Sara E MeyerH Leighton Grimes

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.

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Citations

Aug 3, 2019·British Journal of Haematology·Peter HoklandMarie Bill
Mar 14, 2020·Cancer Cell International·Juan WuJing Wang
Feb 12, 2020·Proceedings of the National Academy of Sciences of the United States of America·Guang LiangRi Cui
Feb 18, 2021·Annals of the New York Academy of Sciences·Jichuan WangBang H Hoang

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Methods Mentioned

BETA
pulldown
transfection
pulldowns
cross-linking immunoprecipitation
AGO-CLIP
RNA-seq
flow cytometry
dissection
ubiquitination
PCR

Software Mentioned

Venny
Ensembl
GO
ToppGene Suite
GraphPad
miRanda
PITA
TopHat
Cytoscape Sets
TargetScan7

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