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

Zhang, L.; Hsu, J. I.; Braekeleer, E. D.; Chen, C.-w.; Patel, T. D.; Urya, H.; Guzman, A. G.; Martell, A. G.; Waldvogel, S. M.; Tovy, A.; Callen, E.; Murdaugh, R. L.; Richard, R. U.; Jansen, S.; Vissers, L.; de Vries, B. B.; Nussenzweig, A.; Huang, S.; Coarfa, C.; Anastas, J. N.; Takahashi, K.; Vassiliou, G. S.; Goodell, M. A.

doi:10.1101/2023.08.31.555634

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bioRxiv · 10.1101/2023.08.31.555634

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

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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 pharmacologic 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 the protective role of SOD1 against oxidative stress in PPM1D-mutant leukemia cells and highlight a new potential therapeutic strategy against PPM1D-mutant cancers.

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Zhang, L., Hsu, J. I., Braekeleer, E. D., Chen, C.-w., Patel, T. D., Urya, H., Guzman, A. G., Martell, A. G., Waldvogel, S. M., Tovy, A., Callen, E., Murdaugh, R. L., Richard, R. U., Jansen, S., Vissers, L., de Vries, B. B., Nussenzweig, A., Huang, S., Coarfa, C., Anastas, J. N., Takahashi, K., Vassiliou, G. S., Goodell, M. A.. 2023-09-01. SOD1 is a synthetic lethal target in PPM1D-mutant leukemia cells. https://doi.org/10.1101/2023.08.31.555634

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