<i>SOD1</i> is a synthetic-lethal target in <i>PPM1D</i>-mutant leukemia cells.

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 <i>PPM1D</i> are found across several human cancers making it a relevant pharmacological target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of <i>PPM1D,</i> uncovering superoxide dismutase-1 (SOD1) as a potential target for <i>PPM1D</i>-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress in <i>PPM1D</i>-mutant cells. Altogether, our results demonstrate a role for SOD1 in the survival of <i>PPM1D</i>-mutant leukemia cells and highlight a new potential therapeutic strategy against <i>PPM1D</i>-mutant cancers.