SOD1is a synthetic lethal target inPPM1D-mutant leukemia cells

Abstract

AbstractThe 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 ofPPM1Dare found across several human cancers making it a relevant pharmacologic target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies ofPPM1D,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 inPPM1D-mutant cells. Altogether, our results demonstrate the protective role of SOD1 against oxidative stress inPPM1D-mutant leukemia cells and highlight a new potential therapeutic strategy againstPPM1D-mutant cancers.