title: A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia.
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.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Tzelepis
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Koike-Yusa
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Etienne
authors.initials: E
authors.lastname: De Braekeleer
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Yilong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Metzakopian
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Dovey
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Mupo
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Vera
authors.initials: V
authors.lastname: Grinkevich
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Milena
authors.initials: M
authors.lastname: Mazan
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Gozdecka
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Ohnishi
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cooper
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Miten
authors.initials: M
authors.lastname: Patel
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: McKerrell
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Haematology, NHS Blood and Transplant, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0PT, UK.
authors.forename: Ana Filipa
authors.initials: AF
authors.lastname: Domingues
authors.affiliation: 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.
authors.forename: Paolo
authors.initials: P
authors.lastname: Gallipoli
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Teichmann
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Hannes
authors.initials: H
authors.lastname: Ponstingl
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
authors.forename: Ultan
authors.initials: U
authors.lastname: McDermott
authors.affiliation: 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.
authors.forename: Julio
authors.initials: J
authors.lastname: Saez-Rodriguez
authors.affiliation: 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.
authors.forename: Brian J P
authors.initials: BJP
authors.lastname: Huntly
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Iorio
authors.affiliation: Department of Haematology, NHS Blood and Transplant, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0PT, UK. Electronic address: cp533@medschl.cam.ac.uk.
authors.forename: Cristina
authors.initials: C
authors.lastname: Pina
authors.affiliation: 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.
authors.forename: George S
authors.initials: GS
authors.lastname: Vassiliou
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK. Electronic address: ky1@sanger.ac.uk.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Yusa
mesh_terms: D000328:Adult; D017209:Apoptosis; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D064112:Clustered Regularly Interspaced Short Palindromic Repeats / Q000235:genetics*; D005820:Genetic Testing; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000628:therapy*; D058990:Molecular Targeted Therapy; D015203:Reproducibility of Results; D000099224:p300-CBP-Associated Factor
chemical_list: D051548:Histone Acetyltransferases; C501179:KAT2A protein, human; D000099224:p300-CBP-Associated Factor
keywords: AML; CRISPR; KAT2A; MB-3; acute myeloid leukemia; genetic screen; genetic vulnerability