PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation.

Journal Article (Journal Article)

The 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.

Full Text

Duke Authors

Cited Authors

  • Khadka, P; Reitman, ZJ; Lu, S; Buchan, G; Gionet, G; Dubois, F; Carvalho, DM; Shih, J; Zhang, S; Greenwald, NF; Zack, T; Shapira, O; Pelton, K; Hartley, R; Bear, H; Georgis, Y; Jarmale, S; Melanson, R; Bonanno, K; Schoolcraft, K; Miller, PG; Condurat, AL; Gonzalez, EM; Qian, K; Morin, E; Langhnoja, J; Lupien, LE; Rendo, V; Digiacomo, J; Wang, D; Zhou, K; Kumbhani, R; Guerra Garcia, ME; Sinai, CE; Becker, S; Schneider, R; Vogelzang, J; Krug, K; Goodale, A; Abid, T; Kalani, Z; Piccioni, F; Beroukhim, R; Persky, NS; Root, DE; Carcaboso, AM; Ebert, BL; Fuller, C; Babur, O; Kieran, MW; Jones, C; Keshishian, H; Ligon, KL; Carr, SA; Phoenix, TN; Bandopadhayay, P

Published Date

  • February 1, 2022

Published In

Volume / Issue

  • 13 / 1

Start / End Page

  • 604 -

PubMed ID

  • 35105861

Pubmed Central ID

  • PMC8807747

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-022-28198-8

Language

  • eng

Conference Location

  • England