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

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2018 Feb 27

PMID 29478914

Citations 66

Authors

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 Akashi

Daniel E Bauer

Takahiro Maeda

Affiliations

Soon will be listed here.

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.

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