Cell Reports (Oct 2016)
A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia
- Konstantinos Tzelepis,
- Hiroko Koike-Yusa,
- Etienne De Braekeleer,
- Yilong Li,
- Emmanouil Metzakopian,
- Oliver M. Dovey,
- Annalisa Mupo,
- Vera Grinkevich,
- Meng Li,
- Milena Mazan,
- Malgorzata Gozdecka,
- Shuhei Ohnishi,
- Jonathan Cooper,
- Miten Patel,
- Thomas McKerrell,
- Bin Chen,
- Ana Filipa Domingues,
- Paolo Gallipoli,
- Sarah Teichmann,
- Hannes Ponstingl,
- Ultan McDermott,
- Julio Saez-Rodriguez,
- Brian J.P. Huntly,
- Francesco Iorio,
- Cristina Pina,
- George S. Vassiliou,
- Kosuke Yusa
Affiliations
- Konstantinos Tzelepis
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
- Hiroko Koike-Yusa
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
- Etienne De Braekeleer
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
- Yilong Li
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
- Emmanouil Metzakopian
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
- Oliver M. Dovey
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
- Annalisa Mupo
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
- Vera Grinkevich
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
- Meng Li
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
- Milena Mazan
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
- Malgorzata Gozdecka
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
- Shuhei Ohnishi
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
- Jonathan Cooper
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
- Miten Patel
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
- Thomas McKerrell
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
- Bin Chen
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
- Ana Filipa Domingues
- Department of Haematology, NHS Blood and Transplant, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0PT, UK
- Paolo Gallipoli
- Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, UK
- Sarah Teichmann
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
- Hannes Ponstingl
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
- Ultan McDermott
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
- Julio Saez-Rodriguez
- European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge CB10 1SD, UK
- Brian J.P. Huntly
- Department of Haematology, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, UK
- Francesco Iorio
- European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge CB10 1SD, UK
- Cristina Pina
- Department of Haematology, NHS Blood and Transplant, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0PT, UK
- George S. Vassiliou
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
- Kosuke Yusa
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK
- DOI
- https://doi.org/10.1016/j.celrep.2016.09.079
- Journal volume & issue
-
Vol. 17,
no. 4
pp. 1193 – 1205
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
