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

Research output: Contribution to journalArticle

24 Citations (Scopus)

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
Pages (from-to)386-400.e5
JournalCancer Cell
Volume33
Issue number3
DOIs
Publication statusPublished - Mar 12 2018

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cell Biology
  • Cancer Research

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    Yamauchi, T., Masuda, T., Canver, M. C., Seiler, M., Semba, Y., Shboul, M., Al-Raqad, M., Maeda, M., Schoonenberg, V. A. C., Cole, M. A., Macias-Trevino, C., Ishikawa, Y., Yao, Q., Nakano, M., Arai, F., Orkin, S. H., Reversade, B., Buonamici, S., Pinello, L., ... Maeda, T. (2018). Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS. Cancer Cell, 33(3), 386-400.e5. https://doi.org/10.1016/j.ccell.2018.01.012