4.8 Article

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

Journal

CANCER CELL
Volume 33, Issue 3, Pages 386-+

Publisher

CELL PRESS
DOI: 10.1016/j.ccell.2018.01.012

Keywords

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Funding

  1. NIDDK [F30DK103359-01A1, K08DK093705, R03DK109232]
  2. JSPS
  3. Agency for Science, Technology, and Research in Singapore
  4. NIH [R00HG008399, P01HL032262, P30DK049216]
  5. NHLBI [DP2OD022716]
  6. Burroughs Wellcome Fund
  7. American Society of Hematology
  8. JSPS [16H06391, 17H01567]
  9. American Cancer Society [RSG-13-379-01-LIB]
  10. American Society of Hematology Bridge Grant
  11. [15J10130]
  12. NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL032262] Funding Source: NIH RePORTER
  13. NATIONAL HUMAN GENOME RESEARCH INSTITUTE [R00HG008399] Funding Source: NIH RePORTER
  14. NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK049216, R03DK109232, R01DK111455, F30DK103359, K08DK093705] Funding Source: NIH RePORTER

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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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