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

Published version
Peer-reviewed

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Authors

Tzelepis, Konstantinos  ORCID logo  https://orcid.org/0000-0002-4865-7648
Koike-Yusa, H 
De Braekeleer, E 
Li, Y 
Metzakopian, E 

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.

Description

Keywords

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

Journal Title

Cell Reports

Conference Name

Journal ISSN

2211-1247
2211-1247

Volume Title

17

Publisher

Elsevier (Cell Press)
Sponsorship
Kay Kendall Leukaemia Fund (KKL888)
Medical Research Council (MR/M010392/1)
Medical Research Council (MC_PC_12009)
European Research Council (647685)
Wellcome Trust (109967/Z/15/Z)
Worldwide Cancer Research (None)
This work was funded by the Kay Kendall Leukaemia Fund (KKLF) and the Wellcome Trust (WT098051). G.S.V. is funded by a Wellcome Trust Senior Fellowship in Clinical Science (WT095663MA) and work in his laboratory is funded by Bloodwise. C.P. is funded by a Kay Kendall Leukaemia Fund Intermediate Fellowship (KKL888).