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

Cell Reports

Paolo Gallipoli¹  Brian J.P. Huntly¹  Ana Filipa Domingues²  Cristina Pina²  Francesco Iorio³  Julio Saez-Rodriguez³  Jonathan Cooper⁴  Kosuke Yusa⁴  Oliver M. Dovey⁴  Hiroko Koike-Yusa⁴  Malgorzata Gozdecka⁴  Vera Grinkevich⁴  Miten Patel⁴  George S. Vassiliou⁴  Ultan McDermott⁴  Sarah Teichmann⁴  Shuhei Ohnishi⁴  Annalisa Mupo⁴  Meng Li⁴  Yilong Li⁴  Konstantinos Tzelepis⁴  Milena Mazan⁴  Emmanouil Metzakopian⁴  Hannes Ponstingl⁴  Bin Chen⁴  Thomas McKerrell⁴  Etienne De Braekeleer⁴ 

[1] Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, UK;Department of Haematology, NHS Blood and Transplant, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0PT, UK;European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge CB10 1SD, UK;Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK;

关键词: CRISPR;    genetic screen;    genetic vulnerability;    acute myeloid leukemia;    AML;    KAT2A;    MB-3;   

DOI  :  10.1016/j.celrep.2016.09.079

来源: DOAJ

【 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.

【 授权许可】

Unknown