PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation.
Loading...
Embargo End Date
ICR Authors
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
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
Document Type
Journal Article
Date
2022-02-01
Date Accepted
2022-01-07
Abstract
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.
Citation
Nature Communications, 2022, 13 (1), pp. 604 -
Source Title
Nature Communications
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
2041-1723
2041-1723