PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation
Nat Commun.
2022-02;
Prasidda Khadka, Zachary J Reitman, Sophie Lu, Graham Buchan, Gabrielle Gionet, Frank Dubois, Diana M Carvalho, Juliann Shih, Shu Zhang, Noah F Greenwald, Travis Zack, Ofer Shapira, Kristine Pelton, Rachel Hartley, Heather Bear, Yohanna Georgis, Spandana Jarmale, Randy Melanson, Kevin Bonanno, Kathleen Schoolcraft, Peter G Miller, Alexandra L Condurat, Elizabeth M Gonzalez, Kenin Qian, Eric Morin, Jaldeep Langhnoja, Leslie E Lupien, Veronica Rendo, Jeromy Digiacomo, Dayle Wang, Kevin Zhou, Rushil Kumbhani, Maria E Guerra Garcia, Claire E Sinai, Sarah Becker, Rachel Schneider, Jayne Vogelzang, Karsten Krug, Amy Goodale, Tanaz Abid, Zohra Kalani, Federica Piccioni, Rameen Beroukhim, Nicole S Persky, David E Root, Angel M Carcaboso, Benjamin L Ebert, Christine Fuller, Ozgun Babur, Mark W Kieran, Chris Jones, Hasmik Keshishian, Keith L Ligon, Steven A Carr, Timothy N Phoenix, Pratiti Bandopadhayay
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PPM1D?truncated phosphatase-dead (PPM1Dtr-D314A) constructs were synthesized as Gateway-compatible entry clones with GenScript |
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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 re... More
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.
