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

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.
AuthorsTakuji 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 Akashi, Daniel E Bauer, Takahiro Maeda
JournalCancer cell (Cancer Cell) Vol. 33 Issue 3 Pg. 386-400.e5 (03 12 2018) ISSN: 1878-3686 [Electronic] United States
PMID29478914 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2018 Elsevier Inc. All rights reserved.
Chemical References
  • 5-((1-(2,6-dichlorobenzyl)piperidin-4-yl)methoxy)quinazoline-2,4-diamine
  • Quinazolines
  • RNA Precursors
  • RNA, Messenger
  • Endoribonucleases
  • DcpS protein, human
Topics
  • Animals
  • CRISPR-Cas Systems (drug effects, genetics)
  • Cell Line
  • Endoribonucleases (drug effects, genetics, metabolism)
  • Humans
  • Leukemia (drug therapy, genetics)
  • Male
  • Metabolic Networks and Pathways (drug effects)
  • Mice, Inbred C57BL
  • Muscular Atrophy, Spinal (drug therapy, genetics)
  • Quinazolines (pharmacology)
  • RNA Precursors (drug effects, genetics)
  • RNA Splicing (drug effects, genetics)
  • RNA, Messenger (genetics)

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