PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation.
Date
2022-02-01ICR Author
Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Adolescent
Adult
Animals
Brain Stem Neoplasms
Carcinogenesis
Cell Cycle
Child
Child, Preschool
DNA Damage
Disease Models, Animal
Female
Glioma
HEK293 Cells
Humans
Infant
Male
Mice
Mutation
Oncogenes
Protein Phosphatase 2C
Proto-Oncogene Proteins c-mdm2
Transcriptome
Tumor Suppressor Protein p53
Young Adult
Language
eng
Date accepted
2022-01-07
License start date
2022-02-01
Citation
Nature Communications, 2022, 13 (1), pp. 604 -
Publisher
NATURE PORTFOLIO