Related Experiment Video
Updated: Jul 16, 2025
Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence
Published on: January 7, 2019
SOD1 is a synthetic lethal target in PPM1D-mutant leukemia cells
Linda Zhang1,2,3,4,5, Joanne I Hsu1,2,3, Etienne D Braekeleer6
1Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, TX.
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.
Insights
Researchers identified superoxide dismutase-1 (SOD1) as a synthetic-lethal target for cancer cells with PPM1D mutations. SOD1 protects PPM1D-mutant leukemia cells from oxidative stress, offering a new therapeutic strategy.
Area of Science:
- Molecular Biology
- Cancer Biology
- Genetics
Background:
- The DNA damage response is crucial for genome stability and is frequently altered in cancer.
- PPM1D (protein phosphatase, Mg2+/Mn2+ dependent 1D) acts as a key negative regulator of this response.
- Gain-of-function mutations and amplifications of PPM1D are prevalent in various human cancers, positioning it as a significant therapeutic target.
Approach:
- CRISPR/Cas9 screening was employed to identify synthetic-lethal interactions with PPM1D.
- This screening identified superoxide dismutase-1 (SOD1) as a potential vulnerability in PPM1D-mutant cells.
- The study investigated the redox landscape and oxidative stress response in PPM1D-mutant cells.
Key Points:
- PPM1D-mutant cells exhibit a dysregulated redox environment with increased reactive oxygen species.
- These cells show a diminished capacity to cope with oxidative stress.
- SOD1 was found to play a protective role against oxidative stress in PPM1D-mutant leukemia cells.
Conclusions:
- SOD1 acts as a critical protective factor against oxidative stress in PPM1D-mutant leukemia.
- Targeting SOD1 presents a novel therapeutic avenue for cancers harboring PPM1D mutations.
- This research uncovers a synthetic-lethal dependency that can be exploited for cancer treatment.
Related Concept Videos
02:23Abnormal Proliferation
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:41Lethal Alleles
Lucien Cuénot discovered lethal alleles in 1905 while studying the inheritance of coat color in mice. The agouti gene is responsible for the color of the coat in mice. This gene codes for an agouti-signaling protein, which is responsible for melanin distribution in mammals. The wild-type allele gives rise to gray-brown coat color in mice, while the mutant allele gives rise to yellow coat color. In addition to coat color, the agouti gene is associated with the yellow...