SOD1 is a synthetic-lethal target in PPM1D -mutant leukemia cells.
Linda ZhangJoanne I HsuEtienne D BraekeleerChun-Wei ChenTajhal D PatelAlejandra G MartellAnna G GuzmanKatharina WohlanSarah M WaldvogelHidetaka UryuAyala TovyElsa CallenRebecca L MurdaughRosemary RichardSandra JansenLisenka VissersBert B A de VriesAndre NussenzweigShixia HuangCristian CoarfaJamie AnastasKoichi TakahashiGeorge S VassiliouMargaret A GoodellPublished in: eLife (2024)
The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase Mg 2+ /Mn 2+ -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.
Keyphrases
- induced apoptosis
- cell cycle arrest
- oxidative stress
- crispr cas
- dna damage response
- endoplasmic reticulum stress
- cell death
- reactive oxygen species
- bone marrow
- acute myeloid leukemia
- dna damage
- transcription factor
- nitric oxide
- single cell
- dna methylation
- dna repair
- hydrogen peroxide
- cell proliferation
- pi k akt
- risk assessment
- resting state
- young adults
- amino acid
- metal organic framework
- heat shock