SOD1 is a synthetic lethal target in PPM1D-mutant leukemia cells-Reference-Cited by-同舟云学术

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

Published:2023-10-04 Issue: Volume: Page:
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Author:

Zhang Linda¹²³⁴⁵^ORCID,Hsu Joanne I.¹²³^ORCID,Braekeleer Etienne D.⁶^ORCID,Chen Chun-Wei³⁴⁵⁷^ORCID,Patel Tajhal D.⁸,Urya Hidetaka⁹,Guzman Anna G.⁴,Martell Alejandra G.⁴,Waldvogel Sarah M.²³⁴⁵¹⁰^ORCID,Tovy Ayala³⁴⁵,Callen Elsa¹¹,Murdaugh Rebecca³⁴⁵¹²,Richard Rosemary³⁴⁵¹²,Jansen Sandra¹³^ORCID,Vissers Lisenka¹³^ORCID,de Vries Bert B.A.¹³^ORCID,Nussenzweig Andre¹⁰,Huang Shixia⁴¹⁴^ORCID,Coarfa Cristian⁴^ORCID,Anastas Jamie N.³⁴⁵¹²^ORCID,Takahashi Koichi⁹¹⁴^ORCID,Vassiliou George⁶^ORCID,Goodell Margaret A.³⁴⁵^ORCID

Affiliation:

1. Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, TX

2. Medical Scientist Training Program, Baylor College of Medicine, Houston, TX

3. Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston TX

4. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX

5. Center for Cell and Gene Therapy, Houston, TX

6. Department of Haematology, Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge

7. Integrated Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, TX

8. Texas Children’s Hospital Department of Hematology/Oncology, Baylor College of Medicine, Houston, TX

9. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX

10. Cancer and Cell Biology Graduate Program, Baylor College of Medicine, Houston, TX

11. Laboratory of Genome Integrity, National Cancer Institute, National Institute of Health, Bethesda, MD

12. Department of Neurosurgery, Baylor College of Medicine, Houston, TX

13. Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands

14. Department of Education, Innovation and Technology, Advanced Technology Cores

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. Moreover, we observed marked genomic instability in mutant cells, which is exacerbated upon inhibition of SOD1. Altogether, our results demonstrate the protective role of SOD1 against oxidative stress and DNA damage in PPM1D-mutant leukemia cells and highlight a new potential therapeutic strategy against PPM1D-mutant cancers.

Publisher

eLife Sciences Publications, Ltd