A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia
Authors
Koike-Yusa, H
De Braekeleer, Etienne
Li, Y
Metzakopian, Emmanouil
Dovey, OM
Grinkevich, V
Li, M
Mazan, M
Gozdecka, M
Ohnishi, S
Cooper, J
Patel, M
Chen, B
Domingues, AF
Ponstingl, H
McDermott, U
Saez-Rodriguez, J
Iorio, F
Yusa, K
Publication Date
2016-10-18Journal Title
Cell Reports
ISSN
2211-1247
Publisher
Elsevier (Cell Press)
Volume
17
Issue
4
Pages
1193-1205
Language
English
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Tzelepis, K., Koike-Yusa, H., De Braekeleer, E., Li, Y., Metzakopian, E., Dovey, O., Mupo, A., et al. (2016). A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia. Cell Reports, 17 (4), 1193-1205. https://doi.org/10.1016/j.celrep.2016.09.079
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 $\textit{DOT1L}$, $\textit{BCL2}$, and $\textit{MEN1}$, and many other genes including clinically actionable candidates. We validate selected genes using genetic and pharmacological inhibition, and chose $\textit{KAT2A}$ as a candidate for downstream study. $\textit{KAT2A}$ 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
CRISPR, genetic screen, genetic vulnerability, acute myeloid leukemia, AML, KAT2A, MB-3
Sponsorship
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).
Funder references
Kay Kendall Leukaemia Fund (KKL888)
Medical Research Council (MR/M010392/1)
MRC (MC_PC_12009)
ECH2020 EUROPEAN RESEARCH COUNCIL (ERC) (647685)
WELLCOME TRUST (109967/Z/15/Z)
Worldwide Cancer Research (14-1069)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1016/j.celrep.2016.09.079
This record's URL: https://www.repository.cam.ac.uk/handle/1810/261423
Rights
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International