SOD1 is a synthetic-lethal target in PPM1D-mutant leukemia cells

Elife. 2024 Jun 18:12:RP91611. doi: 10.7554/eLife.91611.

Abstract

The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase Mg2+/Mn2+-dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications of PPM1D are found across several human cancers making it a relevant pharmacological target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of PPM1D, uncovering superoxide dismutase-1 (SOD1) as a potential target for PPM1D-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress in PPM1D-mutant cells. Altogether, our results demonstrate a role for SOD1 in the survival of PPM1D-mutant leukemia cells and highlight a new potential therapeutic strategy against PPM1D-mutant cancers.

Keywords: DNA damage; cancer; cancer biology; cell biology; leukemia; mouse.

MeSH terms

  • CRISPR-Cas Systems
  • Cell Line, Tumor
  • Humans
  • Leukemia / genetics
  • Mutation
  • Oxidative Stress
  • Protein Phosphatase 2C* / genetics
  • Protein Phosphatase 2C* / metabolism
  • Reactive Oxygen Species / metabolism
  • Superoxide Dismutase-1* / genetics
  • Superoxide Dismutase-1* / metabolism
  • Synthetic Lethal Mutations

Substances

  • Protein Phosphatase 2C
  • PPM1D protein, human
  • Superoxide Dismutase-1
  • SOD1 protein, human
  • Reactive Oxygen Species

Associated data

  • GEO/GSE240874