{Reference Type}: Journal Article
{Title}: SOD1 is a synthetic-lethal target in PPM1D-mutant leukemia cells.
{Author}: Zhang L;Hsu JI;Braekeleer ED;Chen CW;Patel TD;Martell AG;Guzman AG;Wohlan K;Waldvogel SM;Uryu H;Tovy A;Callen E;Murdaugh RL;Richard R;Jansen S;Vissers L;de Vries BBA;Nussenzweig A;Huang S;Coarfa C;Anastas J;Takahashi K;Vassiliou G;Goodell MA;
{Journal}: Elife
{Volume}: 12
{Issue}: 0
{Year}: 2024 Jun 18
{Factor}: 8.713
{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.