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

Cancer Cell
Takuji YamauchiTakahiro Maeda

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.

Citations

Apr 17, 2018·Human Molecular Genetics·Cui ZhangJinfu Wang
Sep 14, 2018·Leukemia·Shinichi KotaniHideki Makishima
Nov 23, 2019·Wiley Interdisciplinary Reviews. RNA·Mariavittoria PizzingaAnne E Willis
Jun 9, 2019·Journal of Hematology & Oncology·Wen-Tao WangYue-Qin Chen
Jan 15, 2019·Cancer Cell International·Debarati GhoshSonali Bhattacharjee
May 16, 2020·International Journal of Molecular Sciences·Konstantin SchuschelJessica I Hoell
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