miR-196b target screen reveals mechanisms maintaining leukemia stemness with therapeutic potential.
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 (p27) 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 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 and inhibited human AML growth. This work illustrates that understanding oncogenic miRNA target pathways can identify actionable targets in leukemia.
|Year of Publication||
J Exp Med
2018 08 06
|PubMed Central ID||
P30 CA056036 / CA / NCI NIH HHS / United States
R01 CA159845 / CA / NCI NIH HHS / United States
R01 CA196658 / CA / NCI NIH HHS / United States
T32 ES007250 / ES / NIEHS NIH HHS / United States