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

Author

Listed:
  • Prasidda Khadka

    (Dana Farber Cancer Institute
    Broad Institute of MIT and Harvard
    Harvard University)

  • Zachary J. Reitman

    (Duke University
    Duke University
    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
    Broad Institute of MIT and Harvard)

  • 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
    Dana-Farber Cancer Institute)

  • Alexandra L. Condurat

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center)

  • Elizabeth M. Gonzalez

    (Broad Institute of MIT and Harvard
    Dana-Farber/Boston Children’s Cancer and Blood Disorders Center)

  • 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
    Broad Institute of MIT and Harvard)

  • 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
    Dana-Farber Cancer Institute
    Howard Hughes Medical Institute)

  • 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
    Bristol Myers Squibb, Boston)

  • 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
    Cincinnati Children’s Hospital Medical Center)

  • Pratiti Bandopadhayay

    (Broad Institute of MIT and Harvard
    Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
    Harvard Medical School)

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.

Suggested Citation

  • 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 & Kri, 2022. "PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28198-8
    DOI: 10.1038/s41467-022-28198-8
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