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

• DOI: 10.1016/j.ccell.2018.01.012
• Publication Date: 2018-02-22T13:14:44Z
• Authors: Takuji Yamauchi; Takeshi Masuda; Matthew C. Canver; Michael Seiler; Yuichiro Semba; Mohammad Shboul; Mohammed Al-Raqad; Manami Maeda; Vivien A.C. Schoo...; Mitchel A. Cole; Claudio Macias-Tr...; Yuichi Ishikawa; Qiuming Yao; Michitaka Nakano; Fumio Arai; Stuart H. Orkin; Bruno Reversade; Silvia Buonamici; Luca Pinello; Koichi Akashi; Daniel E. Bauer; Takahiro Maeda
• Keywords: Male; 0303 health sciences; Leukemia; RNA Splicing; Cell Line; 3. Good health; Mice, Inbred C57BL; Muscular Atrophy, Spinal; 03 medical and health sciences; Endoribonucleases; Quinazolines; RNA Precursors; Animals; Humans; RNA, Messenger; CRISPR-Cas Systems; Metabolic Networks and Pathways

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.