| Literature DB >> 29478914 |
Takuji Yamauchi1, Takeshi Masuda2, Matthew C Canver3, Michael Seiler4, Yuichiro Semba5, Mohammad Shboul6, Mohammed Al-Raqad7, Manami Maeda8, Vivien A C Schoonenberg3, Mitchel A Cole3, Claudio Macias-Trevino3, Yuichi Ishikawa8, Qiuming Yao9, Michitaka Nakano5, Fumio Arai10, Stuart H Orkin3, Bruno Reversade6, Silvia Buonamici4, Luca Pinello9, Koichi Akashi11, Daniel E Bauer3, Takahiro Maeda12.
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.Entities:
Keywords: CRISPR-Cas9 saturation mutagenesis; acute myeloid leukemia; decapping enzyme; drug repurposing; genome-wide CRISPR-Cas9 screening; mRNA decay; pre-mRNA metabolism; pre-mRNA splicing
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Year: 2018 PMID： 29478914 PMCID： PMC5849534 DOI： 10.1016/j.ccell.2018.01.012
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743