eLife (Jun 2024)
SOD1 is a synthetic-lethal target in PPM1D-mutant leukemia cells
- Linda Zhang,
- Joanne I Hsu,
- Etienne D Braekeleer,
- Chun-Wei Chen,
- Tajhal D Patel,
- Alejandra G Martell,
- Anna G Guzman,
- Katharina Wohlan,
- Sarah M Waldvogel,
- Hidetaka Uryu,
- Ayala Tovy,
- Elsa Callen,
- Rebecca L Murdaugh,
- Rosemary Richard,
- Sandra Jansen,
- Lisenka Vissers,
- Bert BA de Vries,
- Andre Nussenzweig,
- Shixia Huang,
- Cristian Coarfa,
- Jamie Anastas,
- Koichi Takahashi,
- George Vassiliou,
- Margaret A Goodell
Affiliations
- Linda Zhang
- ORCiD
- Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, United States; Medical Scientist Training Program, Baylor College of Medicine, Houston, United States; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States; Center for Cell and Gene Therapy, Houston, United States
- Joanne I Hsu
- Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, United States; Medical Scientist Training Program, Baylor College of Medicine, Houston, United States; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States
- Etienne D Braekeleer
- Department of Haematology, Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
- Chun-Wei Chen
- Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States; Center for Cell and Gene Therapy, Houston, United States; Integrated Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, United States
- Tajhal D Patel
- Texas Children’s Hospital Department of Hematology/Oncology, Baylor College of Medicine, Houston, United States
- Alejandra G Martell
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States
- Anna G Guzman
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States
- Katharina Wohlan
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States
- Sarah M Waldvogel
- Medical Scientist Training Program, Baylor College of Medicine, Houston, United States; Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States; Center for Cell and Gene Therapy, Houston, United States; Cancer and Cell Biology Graduate Program, Baylor College of Medicine, Houston, United States
- Hidetaka Uryu
- ORCiD
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States
- Ayala Tovy
- Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States; Center for Cell and Gene Therapy, Houston, United States
- Elsa Callen
- Laboratory of Genome Integrity, National Cancer Institute, National Institute of Health, Bethesda, United States
- Rebecca L Murdaugh
- Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States; Center for Cell and Gene Therapy, Houston, United States; Department of Neurosurgery, Baylor College of Medicine, Houston, United States
- Rosemary Richard
- Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States; Center for Cell and Gene Therapy, Houston, United States; Department of Neurosurgery, Baylor College of Medicine, Houston, United States
- Sandra Jansen
- Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, Netherlands
- Lisenka Vissers
- Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, Netherlands
- Bert BA de Vries
- Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, Netherlands
- Andre Nussenzweig
- Laboratory of Genome Integrity, National Cancer Institute, National Institute of Health, Bethesda, United States
- Shixia Huang
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States; Department of Education, Innovation and Technology, Advanced Technology Cores, University of Texas, Houston, United States
- Cristian Coarfa
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States
- Jamie Anastas
- Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States; Center for Cell and Gene Therapy, Houston, United States; Department of Neurosurgery, Baylor College of Medicine, Houston, United States
- Koichi Takahashi
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, United States; Department of Genome Medicine, The University of Texas MD Anderson Cancer Center, Houston, United States
- George Vassiliou
- ORCiD
- Department of Haematology, Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom
- Margaret A Goodell
- ORCiD
- Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, United States; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States; Center for Cell and Gene Therapy, Houston, United States
- DOI
- https://doi.org/10.7554/eLife.91611
- Journal volume & issue
-
Vol. 12
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.
Keywords
