Genome-wide CRISPR-Cas9 Screens Reveal Loss of Redundancy between PKMYT1 and WEE1 in Glioblastoma Stem-like Cells

被引：162

作者：

Toledo, Chad M. ^{[1
,2
]}

Ding, Yu ^{[1
]}

Hoellerbauer, Pia ^{[1
,2
]}

Davis, Ryan J. ^{[1
,2
,3
]}

Basom, Ryan ^{[4
]}

Girard, Emily J. ^{[3
]}

Lee, Eunjee ^{[5
]}

Corrin, Philip ^{[1
]}

Hart, Traver ^{[6
,7
,8
]}

Bolouri, Hamid ^{[1
]}

Davison, Jerry ^{[4
]}

Zhang, Qing ^{[4
]}

Hardcastle, Justin ^{[1
]}

Aronow, Bruce J. ^{[9
]}

Plaisier, Christopher L. ^{[10
]}

Baliga, Nitin S. ^{[10
]}

Moffat, Jason ^{[6
,7
,8
]}

Lin, Qi ^{[11
]}

Li, Xiao-Nan ^{[11
]}

Nam, Do-Hyun ^{[12
]}

Lee, Jeongwu ^{[13
]}

Pollard, Steven M. ^{[14
,15
]}

Zhu, Jun ^{[5
]}

Delrow, Jeffery J. ^{[4
]}

Clurman, Bruce E. ^{[1
,3
]}

Olson, James M. ^{[3
]}

Paddison, Patrick J. ^{[1
,2
]}

机构：

[1] Fred Hutchinson Canc Res Ctr, Human Biol Div, Seattle, WA 98109 USA

[2] Univ Washington, Mol & Cellular Biol Program, Seattle, WA 98195 USA

[3] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA

[4] Fred Hutchinson Canc Res Ctr, Genom & Bioinformat Shared Resources, Seattle, WA 98109 USA

[5] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, Dept Genet & Genom Sci, New York, NY 10029 USA

[6] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 3E1, Canada

[7] Donnelly Ctr, Toronto, ON M5S 3E1, Canada

[8] Canadian Inst Adv Res, Toronto, ON M5G 1Z8, Canada

[9] Cincinnati Childrens Hosp Med Ctr, Div Biomed Informat, Cincinnati, OH 45229 USA

[10] Inst Syst Biol, Seattle, WA 98109 USA

[11] Baylor Coll Med, Dept Pediat, Brain Tumor Program, Texas Childrens Canc Ctr, Houston, TX 77030 USA

[12] Samsung Med Ctr, Inst Refractory Canc Res, Seoul 135710, South Korea

[13] Cleveland Clin, Lerner Res Inst, Dept Stem Cell Biol & Regenerat Med, Cleveland, OH 44192 USA

[14] Univ Edinburgh, Edinburgh CRUK Canc Res Ctr, Edinburgh EH16 4UU, Midlothian, Scotland

[15] Univ Edinburgh, MRC Ctr Regenerat Med, Edinburgh EH16 4UU, Midlothian, Scotland

来源：

CELL REPORTS | 2015年 / 13卷 / 11期

基金：

美国国家科学基金会;

关键词：

INHIBITORY KINASE; PHOSPHORYLATES CDC2; GENE-EXPRESSION; RNAI SCREEN; HUMAN MYT1; BRAIN; PROTEIN; GOLGI; REQUIREMENT; ACTIVATION;

D O I：

10.1016/j.celrep.2015.11.021

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页码：2425 / 2439

页数：15

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