PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation
Copyright policy )PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation
AbstractThe role of PPM1D mutations in de novo gliomagenesis has not been systematically explored. Here we analyze whole genome sequences of 170 pediatric high-grade gliomas and find that truncating mutations in PPM1D that increase the stability of its phosphatase are clonal driver events in 11% of Diffuse Midline Gliomas (DMGs) and are enriched in primary pontine tumors. Through the development of DMG mouse models, we show that PPM1D mutations potentiate gliomagenesis and that PPM1D phosphatase activity is required for in vivo oncogenesis. Finally, we apply integrative phosphoproteomic and functional genomics assays and find that oncogenic effects of PPM1D truncation converge on regulators of cell cycle, DNA damage response, and p53 pathways, revealing therapeutic vulnerabilities including MDM2 inhibition.
- Duke University United States
- Institute of Cancer Research United Kingdom
- University of Massachusetts System United States
- Cincinnati Children's Hospital Medical Center United States
- University of Cincinnati United States
Adult, Male, Adolescent, Carcinogenesis, Science, 610, Article, Young Adult, Mice, Animals, Brain Stem Neoplasms, Humans, Preschool, Child, Animal, Q, Cell Cycle, Infant, Proto-Oncogene Proteins c-mdm2, Glioma, Oncogenes, Protein Phosphatase 2C, Disease Models, Animal, HEK293 Cells, Child, Preschool, Disease Models, Mutation, Female, Tumor Suppressor Protein p53, Transcriptome, DNA Damage
Adult, Male, Adolescent, Carcinogenesis, Science, 610, Article, Young Adult, Mice, Animals, Brain Stem Neoplasms, Humans, Preschool, Child, Animal, Q, Cell Cycle, Infant, Proto-Oncogene Proteins c-mdm2, Glioma, Oncogenes, Protein Phosphatase 2C, Disease Models, Animal, HEK293 Cells, Child, Preschool, Disease Models, Mutation, Female, Tumor Suppressor Protein p53, Transcriptome, DNA Damage
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