Journal
CELL REPORTS
Volume 13, Issue 11, Pages 2425-2439Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2015.11.021
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Funding
- National Science Foundation [DGE-0-718124, DGE-1256082]
- Interdisciplinary Training in Cancer Research [T32CA080416]
- NCI/NIH [R01CA084069-11, R01CA155360, R01CA114567, R01CA190957, R21CA170722, P30CA15704]
- DoD Translational New Investigator Award [CA100735]
- Pew Biomedical Scholars Program
- Phi Beta Psi Sorority Cancer Research Grant
- CDMRP [545629, CA100735] Funding Source: Federal RePORTER
- Cancer Research UK [19680, 17368] Funding Source: researchfish
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To identify therapeutic targets for glioblastoma (GBM), we performed genome-wide CRISPR-Cas9 knockout (KO) screens in patient-derived GBM stem-like cells (GSCs) and human neural stem/progenitors (NSCs), non-neoplastic stem cell controls, for genes required for their in vitro growth. Surprisingly, the vast majority GSC-lethal hits were found outside of molecular networks commonly altered in GBM and GSCs (e.g., oncogenic drivers). In vitro and in vivo validation of GSC-specific targets revealed several strong hits, including the wee1-like kinase, PKMYT1/Myt1. Mechanistic studies demonstrated that PKMYT1 acts redundantly with WEE1 to inhibit cyclin B-CDK1 activity via CDK1-Y15 phosphorylation and to promote timely completion of mitosis in NSCs. However, in GSCs, this redundancy is lost, most likely as a result of oncogenic signaling, causing GBM-specific lethality.
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