SOD1 Is a Synthetic Lethal Target in PPM1D-Mutant Leukemia Cells

Authors

• 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 Urya
• Ayala Tovy
• Elsa Callen
• Rebecca Murdaugh
• Rosemary Richard
• Sandra Jansen
• Lisenka Vissers
• Bert B A de Vries
• Andre Nussenzweig
• Shixia Huang
• Cristian Coarfa
• Jamie N Anastas
• Koichi Takahashi
• George Vassiliou
• Margaret A Goodell

Language

English

Publication Date

1-17-2024

Journal

bioRxiv

DOI

10.1101/2023.08.31.555634

PMID

37693622

PMCID

PMC10491179

PubMedCentral® Posted Date

1-17-2024

PubMedCentral® Full Text Version

Post-print

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.

Published Open-Access

yes

Recommended Citation

Zhang, Linda; Hsu, Joanne I; Braekeleer, Etienne D; et al., "SOD1 Is a Synthetic Lethal Target in PPM1D-Mutant Leukemia Cells" (2024). Faculty, Staff and Students Publications. 7957.
https://digitalcommons.library.tmc.edu/baylor_docs/7957