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Title: A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia
Authors: Tzelepis, K
Koike-Yusa, H
De Braekeleer, E
Li, Y
Metzakopian, E
Dovey, OM
Mupo, A
Grinkevich, V
Li, M
Mazan, M
Gozdecka, M
Ohnishi, S
Cooper, J
Patel, M
McKerrell, T
Chen, B
Domingues, AF
Gallipoli, P
Teichmann, S
Ponstingl, H
McDermott, U
Saez-Rodriguez, J
Huntly, BJP
Iorio, F
Pina, C
Vassiliou, GS
Yusa, K
Keywords: CRISPR;Genetic screen;Genetic vulnerability;Acute myeloid leukemia;AML;KAT2A MB-3
Issue Date: 18-Oct-2016
Publisher: Cell Press
Citation: Tzelepis K, Koike-Yusa H, De Braekeleer E, Li Y, Metzakopian E, Dovey OM, Mupo A, Grinkevich V, Li M, Mazan M, Gozdecka M. A CRISPR dropout screen identifies genetic vulnerabilities and therapeutic targets in acute myeloid leukemia. Cell reports. 2016 Oct 18;17(4):1193-205.
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.
ISSN: 2211-1247
Appears in Collections:Dept of Life Sciences Research Papers

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