A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia

被引：464

作者：

Tzelepis, Konstantinos ^{[1
]}

Koike-Yusa, Hiroko ^{[1
]}

De Braekeleer, Etienne ^{[1
]}

Li, Yilong ^{[1
]}

Metzakopian, Emmanouil ^{[1
]}

Dovey, Oliver M. ^{[1
]}

Mupo, Annalisa ^{[1
]}

Grinkevich, Vera ^{[1
]}

Li, Meng ^{[1
]}

Mazan, Milena ^{[1
]}

Gozdecka, Malgorzata ^{[1
]}

Ohnishi, Shuhei ^{[1
]}

Cooper, Jonathan ^{[1
]}

Patel, Miten ^{[1
]}

McKerrell, Thomas ^{[1
]}

Chen, Bin ^{[1
]}

Domingues, Ana Filipa ^{[3
]}

Gallipoli, Paolo ^{[4
,5
]}

Teichmann, Sarah ^{[1
]}

Ponstingl, Hannes ^{[1
]}

McDermott, Ultan ^{[1
]}

Saez-Rodriguez, Julio ^{[2
,6
]}

Huntly, Brian J. P. ^{[4
,5
]}

Iorio, Francesco ^{[2
]}

Pina, Cristina ^{[3
]}

Vassiliou, George S. ^{[1
,4
,5
]}

Yusa, Kosuke ^{[1
]}

机构：

[1] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[2] European Bioinformat Inst, European Mol Biol Lab, Cambridge CB10 1SD, England

[3] Univ Cambridge, NHS Blood & Transplant, Dept Haematol, Cambridge Biomed Campus, Cambridge CB2 0PT, England

[4] Cambridge Univ Hosp NHS Trust, Dept Haematol, Cambridge CB2 0QQ, England

[5] Univ Cambridge, Wellcome Trust MRC Stem Cell Inst, Cambridge Biomed Campus, Cambridge CB2 0XY, England

[6] Rhein Westfal TH Aachen, Joint Res Ctr Computat Biomed, Fac Med, D-52074 Aachen, Germany

来源：

CELL REPORTS | 2016年 / 17卷 / 04期

基金：

英国惠康基金;

关键词：

COPY-NUMBER ALTERATION; HUMAN-CELLS; FUNCTIONAL GENOMICS; DESIGN; INHIBITOR; GCN5; PROLIFERATION; ENDONUCLEASE; METHYLATION; ONCOPROTEIN;

D O I：

10.1016/j.celrep.2016.09.079

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Acute myeloid leukemia (AML) is an aggressive cancer with a poor prognosis, for which mainstream treatments have not changed for decades. To identify additional therapeutic targets in AML, we optimize a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screening platform and use it to identify genetic vulnerabilities in AML cells. We identify 492 AML-specific cell-essential genes, including several established therapeutic targets such as DOT1L, BCL2, and MEN1, and many other genes including clinically actionable candidates. We validate selected genes using genetic and pharmacological inhibition, and chose KAT2A as a candidate for downstream study. KAT2A inhibition demonstrated anti-AML activity by inducing myeloid differentiation and apoptosis, and suppressed the growth of primary human AMLs of diverse genotypes while sparing normal hemopoietic stem-progenitor cells. Our results propose that KAT2A inhibition should be investigated as a therapeutic strategy in AML and provide a large number of genetic vulnerabilities of this leukemia that can be pursued in downstream studies.

引用

页码：1193 / 1205

页数：13

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