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

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 () and Pratiti Bandopadhayay ()
Additional contact information
Prasidda Khadka: Dana Farber Cancer Institute
Zachary J. Reitman: Duke University
Sophie Lu: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Graham Buchan: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Gabrielle Gionet: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Frank Dubois: Dana Farber Cancer Institute
Diana M. Carvalho: Institute of Cancer Research
Juliann Shih: Broad Institute of MIT and Harvard
Shu Zhang: Broad Institute of MIT and Harvard
Noah F. Greenwald: Dana Farber Cancer Institute
Travis Zack: Dana Farber Cancer Institute
Ofer Shapira: Dana Farber Cancer Institute
Kristine Pelton: Dana Farber Cancer Institute
Rachel Hartley: University of Cincinnati
Heather Bear: Cincinnati Children’s Hospital Medical Center
Yohanna Georgis: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Spandana Jarmale: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Randy Melanson: Broad Institute of MIT and Harvard
Kevin Bonanno: Broad Institute of MIT and Harvard
Kathleen Schoolcraft: Dana Farber Cancer Institute
Peter G. Miller: Broad Institute of MIT and Harvard
Alexandra L. Condurat: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Elizabeth M. Gonzalez: Broad Institute of MIT and Harvard
Kenin Qian: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Eric Morin: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Jaldeep Langhnoja: University of Cincinnati
Leslie E. Lupien: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Veronica Rendo: Dana Farber Cancer Institute
Jeromy Digiacomo: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Dayle Wang: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Kevin Zhou: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Rushil Kumbhani: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Maria E. Guerra Garcia: Duke University
Claire E. Sinai: Dana Farber Cancer Institute
Sarah Becker: Dana Farber Cancer Institute
Rachel Schneider: Dana Farber Cancer Institute
Jayne Vogelzang: Dana Farber Cancer Institute
Karsten Krug: Broad Institute of MIT and Harvard
Amy Goodale: Broad Institute of MIT and Harvard
Tanaz Abid: Broad Institute of MIT and Harvard
Zohra Kalani: Broad Institute of MIT and Harvard
Federica Piccioni: Broad Institute of MIT and Harvard
Rameen Beroukhim: Dana Farber Cancer Institute
Nicole S. Persky: Broad Institute of MIT and Harvard
David E. Root: Broad Institute of MIT and Harvard
Angel M. Carcaboso: Institut de Recerca Sant Joan de Deu
Benjamin L. Ebert: Broad Institute of MIT and Harvard
Christine Fuller: Cincinnati Children’s Hospital Medical Center
Ozgun Babur: University of Massachusetts Boston
Mark W. Kieran: Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
Chris Jones: Institute of Cancer Research
Hasmik Keshishian: Broad Institute of MIT and Harvard
Keith L. Ligon: Dana Farber Cancer Institute
Steven A. Carr: Broad Institute of MIT and Harvard
Timothy N. Phoenix: University of Cincinnati
Pratiti Bandopadhayay: Broad Institute of MIT and Harvard

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28198-8

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