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

Cancer Cell. 2018 Mar 12;33(3):386-400.e5. doi: 10.1016/j.ccell.2018.01.012. Epub 2018 Feb 22.


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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CRISPR-Cas Systems / drug effects*
  • CRISPR-Cas Systems / genetics
  • Cell Line
  • Endoribonucleases / drug effects*
  • Endoribonucleases / genetics
  • Endoribonucleases / metabolism
  • Humans
  • Leukemia / drug therapy*
  • Leukemia / genetics
  • Male
  • Metabolic Networks and Pathways / drug effects
  • Mice, Inbred C57BL
  • Muscular Atrophy, Spinal / drug therapy*
  • Muscular Atrophy, Spinal / genetics
  • Quinazolines / pharmacology*
  • RNA Precursors / drug effects
  • RNA Precursors / genetics
  • RNA Splicing / drug effects
  • RNA Splicing / genetics
  • RNA, Messenger / genetics


  • 5-((1-(2,6-dichlorobenzyl)piperidin-4-yl)methoxy)quinazoline-2,4-diamine
  • Quinazolines
  • RNA Precursors
  • RNA, Messenger
  • Endoribonucleases
  • DcpS protein, human