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

The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase Mg /Mn -dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications of are found across several huma...

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Published in:eLife 2024-06, 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 B A, Nussenzweig, Andre, Huang, Shixia, Coarfa, Cristian, Anastas, Jamie, Takahashi, Koichi, Vassiliou, George, Goodell, Margaret A
Format: Article
Language:English
Subjects:
Apoptosis
Cancer
Cancer Biology
Cell Biology
Cell cycle
Cell Line, Tumor
Cloning
CRISPR
CRISPR-Cas Systems
Development and progression
DNA damage
DNA repair
Genes
Genomes
Genomics
Health aspects
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
Superoxide dismutase
Superoxide Dismutase-1 - genetics
Superoxide Dismutase-1 - metabolism
Synthetic Lethal Mutations
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Summary:The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase Mg /Mn -dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications of are found across several human cancers making it a relevant pharmacological target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of uncovering superoxide dismutase-1 (SOD1) as a potential target for -mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress in -mutant cells. Altogether, our results demonstrate a role for SOD1 in the survival of -mutant leukemia cells and highlight a new potential therapeutic strategy against -mutant cancers.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.91611