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

• Published in: eLife Vol. 12
• Main Authors: Zhang, Linda, Hsu, Joanne I, Braekeleer, Etienne D, Chen, Chun-Wei, Patel, Tajhal D, Martell, Alejandra G, Guzman, Anna G, Wohlan, Katharina, Waldvogel, Sarah M, Uryu, Hidetaka, Tovy, Ayala, Callen, Elsa, Murdaugh, Rebecca L, Richard, Rosemary, Jansen, Sandra, Vissers, Lisenka, de Vries, Bert BA, Nussenzweig, Andre, Huang, Shixia, Coarfa, Cristian, Anastas, Jamie, Takahashi, Koichi, Vassiliou, George, Goodell, Margaret A
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 18.06.2024; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Apoptosis; Cancer; Cancer Biology; Cell Biology; Cell cycle; Cell Line, Tumor; Cloning; CRISPR; CRISPR-Cas Systems; DNA damage; Genes; Genomes; Humans; Leukemia; Leukemia - genetics; Leukemia research; Magnesium; Medical prognosis; Mutants; Mutation; Ovaries; Oxidative Stress; Phosphatase; Phosphatases; Physiological aspects; Protein phosphatase; Protein Phosphatase 2C - genetics; Protein Phosphatase 2C - metabolism; Proteins; Reactive oxygen species; Reactive Oxygen Species - metabolism; Superoxide dismutase; Superoxide Dismutase-1 - genetics; Superoxide Dismutase-1 - metabolism; Synthetic Lethal Mutations; United States; leukemia; mouse; cancer; cancer biology; cell biology; DNA damage
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.91611

The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase Mg 2+ /Mn 2+ -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.