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

Takuji Yamauchi1, Takeshi Masuda2, Matthew C Canver3

  • 1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan; Department of Stem Cell Biology and Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan.

Cancer Cell
|February 27, 2018
PubMed

Insights

The scavenger decapping enzyme (DCPS) is crucial for acute myeloid leukemia (AML) cell survival and can be targeted for therapy. Inhibiting DCPS shows anti-leukemic effects without harming normal blood cell development.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • Acute myeloid leukemia (AML) requires novel therapeutic targets.
  • Understanding the genetic vulnerabilities of AML cells is critical for developing new treatments.

Purpose of the Study:

  • To identify novel therapeutic targets for acute myeloid leukemia (AML).
  • To investigate the role of the mRNA decapping enzyme scavenger (DCPS) in AML.
  • To evaluate the potential of DCPS inhibition as an AML therapy.

Main Methods:

  • Genome-wide CRISPR-Cas9 screening in AML cell lines and in vivo.
  • Mass spectrometry to identify protein interactions of DCPS.
  • Testing the efficacy of a DCPS inhibitor (RG3039) in AML models.
  • Analysis of human genetic data for DCPS loss-of-function mutations.

Main Results:

  • The mRNA decapping enzyme scavenger (DCPS) gene was identified as essential for AML cell survival.
  • DCPS interacts with pre-mRNA processing machinery, including spliceosomes.
  • The DCPS inhibitor RG3039 demonstrated anti-leukemic activity by inducing pre-mRNA mis-splicing.
  • Germline loss-of-function mutations in DCPS do not cause hematologic abnormalities in humans.

Conclusions:

  • DCPS is a promising therapeutic target for acute myeloid leukemia (AML).
  • Targeting DCPS offers a strategy for AML treatment with minimal impact on normal hematopoiesis.
  • This study elucidates the role of DCPS in pre-mRNA metabolism and its implications for cancer therapy.
Keywords:
CRISPR-Cas9 saturation mutagenesisacute myeloid leukemiadecapping enzymedrug repurposinggenome-wide CRISPR-Cas9 screeningmRNA decaypre-mRNA metabolismpre-mRNA splicing

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