Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS

Takuji Yamauchi, Takeshi Masuda, Matthew C. Canver, Michael Seiler, Yuichiro Semba, Mohammad Shboul, Mohammed Al-Raqad, Manami Maeda, Vivien A.C. Schoonenberg, Mitchel A. Cole, Claudio Macias-Trevino, Yuichi Ishikawa, Qiuming Yao, Michitaka Nakano, Fumio Arai, Stuart H. Orkin, Bruno Reversade, Silvia Buonamici, Luca Pinello, Koichi AkashiDaniel E. Bauer, Takahiro Maeda*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

To identify novel targets for acute myeloid leukemia (AML) therapy, we performed genome-wide CRISPR-Cas9 screening using AML cell lines, followed by a second screen in vivo. Here, we show that the mRNA decapping enzyme scavenger (DCPS) gene is essential for AML cell survival. The DCPS enzyme interacted with components of pre-mRNA metabolic pathways, including spliceosomes, as revealed by mass spectrometry. RG3039, a DCPS inhibitor originally developed to treat spinal muscular atrophy, exhibited anti-leukemic activity via inducing pre-mRNA mis-splicing. Humans harboring germline biallelic DCPS loss-of-function mutations do not exhibit aberrant hematologic phenotypes, indicating that DCPS is dispensable for human hematopoiesis. Our findings shed light on a pre-mRNA metabolic pathway and identify DCPS as a target for AML therapy. Yamauchi et al. perform in vitro and in vivo CRISPR-Cas9 genetic screening of p53 WT AML to identify potential therapeutic targets. They find that AML relies on the DCPS decapping enzyme, and a DCPS inhibitor shows anti-leukemia activity in tumor models without impacting normal hematopoiesis.

Original languageEnglish (US)
Pages (from-to)386-400.e5
JournalCancer Cell
Volume33
Issue number3
DOIs
StatePublished - Mar 12 2018

Bibliographical note

Funding Information:
We thank Hai Yi, Catherine Zhu, and members in the Division of Hematology at BWH and Department of Medicine and Biosystemic Science at Kyushu University for assistance, advice, and helpful discussion, Zach Herbert for help and advice on sequencing and Elise Lamar for critical reading of the manuscript. This work is supported in part by a Grant-in-Aid for JSPS Fellows ( 15J10130 ) (to T.Y.), an NIDDK Predoctoral National Research Service Award for an MD/PhD Fellowship ( F30DK103359-01A1 ) (to M.C.C.), a JSPS Young Researcher Overseas Visits Program for Vitalizing Brain Circulation Fellowship (to Y.I.), a Strategic Positioning Fund for Genetic Orphan Diseases from the Agency for Science, Technology, and Research in Singapore (to B.R.), NIH R00HG008399 (to L.P.), NIDDK ( K08DK093705 , R03DK109232 ), NHLBI ( DP2OD022716 ), Burroughs Wellcome Fund , and American Society of Hematology (to D.E.B.), NIH P01HL032262 and P30DK049216 grants (Center of Excellence in Molecular Hematology) (to S.H.O.), a JSPS Grant-in-Aid for Scientific Research (S) ( 16H06391 ) (to K.A.), and a JSPS Grant-in-Aid for Scientific Research (A) ( 17H01567 ), American Cancer Society ( RSG-13-379-01-LIB ) and an American Society of Hematology Bridge Grant (to T.M.).

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

  • acute myeloid leukemia
  • CRISPR-Cas9 saturation mutagenesis
  • decapping enzyme
  • drug repurposing
  • genome-wide CRISPR-Cas9 screening
  • mRNA decay
  • pre-mRNA metabolism
  • pre-mRNA splicing

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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