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

Publication Date

6-18-2024

Journal

eLife

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

Protein Phosphatase 2C, Humans, Superoxide Dismutase-1, Cell Line, Tumor, Leukemia, CRISPR-Cas Systems, Oxidative Stress, Reactive Oxygen Species, Synthetic Lethal Mutations, Mutation

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Associated Data

PMID: 38896450