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Cell Rep. 2016 Oct 18;17(4):1193-1205. doi: 10.1016/j.celrep.2016.09.079.

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

Author information

1
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
2
Department of Haematology, NHS Blood and Transplant, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0PT, UK.
3
Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, UK; Wellcome Trust-MRC Stem Cell Institute, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0XY, UK.
4
European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge CB10 1SD, UK; Faculty of Medicine, Joint Research Center for Computational Biomedicine, RWTH Aachen, 52074 Aachen, Germany.
5
European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge CB10 1SD, UK.
6
Department of Haematology, NHS Blood and Transplant, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0PT, UK. Electronic address: cp533@medschl.cam.ac.uk.
7
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, UK; Wellcome Trust-MRC Stem Cell Institute, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0XY, UK. Electronic address: gsv20@sanger.ac.uk.
8
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. Electronic address: ky1@sanger.ac.uk.

Abstract

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.

KEYWORDS:

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

PMID:
27760321
PMCID:
PMC5081405
DOI:
10.1016/j.celrep.2016.09.079
[Indexed for MEDLINE]
Free PMC Article

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