Nature Communications (Feb 2022)
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,
- Pratiti Bandopadhayay
Affiliations
- Prasidda Khadka
- Department of Cancer Biology, Dana Farber Cancer Institute
- Zachary J. Reitman
- Department of Radiation Oncology, 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
- Department of Cancer Biology, Dana Farber Cancer Institute
- Diana M. Carvalho
- Division of Molecular Pathology, Institute of Cancer Research
- Juliann Shih
- Broad Institute of MIT and Harvard
- Shu Zhang
- Broad Institute of MIT and Harvard
- Noah F. Greenwald
- Department of Cancer Biology, Dana Farber Cancer Institute
- Travis Zack
- Department of Cancer Biology, Dana Farber Cancer Institute
- Ofer Shapira
- Department of Cancer Biology, Dana Farber Cancer Institute
- Kristine Pelton
- Department of Oncologic Pathology, Dana Farber Cancer Institute
- Rachel Hartley
- Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati
- Heather Bear
- Research in Patient Services, 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
- Department of Oncologic Pathology, 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
- Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati
- Leslie E. Lupien
- Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
- Veronica Rendo
- Department of Cancer Biology, 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 Cancer Institute, Duke University
- Claire E. Sinai
- Department of Oncologic Pathology, Dana Farber Cancer Institute
- Sarah Becker
- Department of Oncologic Pathology, Dana Farber Cancer Institute
- Rachel Schneider
- Department of Oncologic Pathology, Dana Farber Cancer Institute
- Jayne Vogelzang
- Department of Oncologic Pathology, 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
- Department of Cancer Biology, 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
- Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Deu, Institut de Recerca Sant Joan de Deu
- Benjamin L. Ebert
- Broad Institute of MIT and Harvard
- Christine Fuller
- Department of Pathology, Cincinnati Children’s Hospital Medical Center
- Ozgun Babur
- College of Science and Mathematics, University of Massachusetts Boston
- Mark W. Kieran
- Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
- Chris Jones
- Division of Molecular Pathology, Institute of Cancer Research
- Hasmik Keshishian
- Broad Institute of MIT and Harvard
- Keith L. Ligon
- Department of Oncologic Pathology, Dana Farber Cancer Institute
- Steven A. Carr
- Broad Institute of MIT and Harvard
- Timothy N. Phoenix
- Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati
- Pratiti Bandopadhayay
- Broad Institute of MIT and Harvard
- DOI
- https://doi.org/10.1038/s41467-022-28198-8
- Journal volume & issue
-
Vol. 13,
no. 1
pp. 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.
