@article{00f6cde3b623483e965a2773f6552629,
title = "Genome-wide CRISPR-Cas9 Screens Reveal Loss of Redundancy between PKMYT1 and WEE1 in Glioblastoma Stem-like Cells",
abstract = "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.",
keywords = "CRISPR-Cas9, Cancer therapeutics, Functional genomics, Gene editing, Glioblastoma, Myt1, PKMYT1, WEE1",
author = "Toledo, {Chad M.} and Yu Ding and Pia Hoellerbauer and Davis, {Ryan J.} and Ryan Basom and Girard, {Emily J.} and Eunjee Lee and Philip Corrin and Traver Hart and Hamid Bolouri and Jerry Davison and Qing Zhang and Justin Hardcastle and Aronow, {Bruce J.} and Plaisier, {Christopher L.} and Baliga, {Nitin S.} and Jason Moffat and Qi Lin and Li, {Xiao Nan} and Nam, {Do Hyun} and Jeongwu Lee and Pollard, {Steven M.} and Jun Zhu and Delrow, {Jeffery J.} and Clurman, {Bruce E.} and Olson, {James M.} and Paddison, {Patrick J.}",
note = "Funding Information: We thank Prashant Mali, Eric Holland, Pierre Roger, Cassie Sather, and members of J.M.O.{\textquoteright}s and P.J.P.{\textquoteright}s labs for helpful discussions and Pam Lindberg for administrative assistance. We thank Feng Zhang, Prashant Mali, David Sabatini, Valeri Vasioukhin, and Denise Galloway for providing reagents. We thank Cory McCartan, Chris Yang, and Christina Toledo for assistance with experiments. This work was supported by the following grants: National Science Foundation Graduate Research Fellowship Program ( DGE-0-718124 and DGE-1256082 ) (C.M.T.), Interdisciplinary Training in Cancer Research ( T32CA080416 ) (P.H.), NCI/NIH ( R01CA084069-11 ) (B.E.C.), NCI/NIH ( R01CA155360 ; R01CA114567 ) (J.M.O.), NCI/NIH ( R01CA190957 ; R21CA170722 ; P30CA15704 ) (P.J.P.), DoD Translational New Investigator Award CA100735 (P.J.P.), the Pew Biomedical Scholars Program (P.J.P.), and a Phi Beta Psi Sorority Cancer Research Grant (P.J.P.). Publisher Copyright: {\textcopyright} 2015 The Authors.",
year = "2015",
month = dec,
day = "22",
doi = "10.1016/j.celrep.2015.11.021",
language = "English (US)",
volume = "13",
pages = "2425--2439",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "11",
}
