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

Nat Commun. 2022 Feb 1;13(1):604. doi: 10.1038/s41467-022-28198-8.

Prasidda Khadka ^# ¹ ² ³, Zachary J Reitman ^# ⁴ ⁵ ⁶, Sophie Lu ⁷, Graham Buchan ⁷, Gabrielle Gionet ⁷, Frank Dubois ¹ ², Diana M Carvalho ⁸, Juliann Shih ², Shu Zhang ², Noah F Greenwald ¹, Travis Zack ¹, Ofer Shapira ¹, Kristine Pelton ⁹, Rachel Hartley ¹⁰, Heather Bear ¹¹, Yohanna Georgis ⁷, Spandana Jarmale ⁷, Randy Melanson ², Kevin Bonanno ², Kathleen Schoolcraft ⁹, Peter G Miller ² ¹², Alexandra L Condurat ⁷, Elizabeth M Gonzalez ² ⁷, Kenin Qian ⁷, Eric Morin ⁷, Jaldeep Langhnoja ¹⁰, Leslie E Lupien ⁷, Veronica Rendo ¹, Jeromy Digiacomo ⁷, Dayle Wang ⁷, Kevin Zhou ⁷, Rushil Kumbhani ⁷, Maria E Guerra Garcia ⁵, Claire E Sinai ⁹, Sarah Becker ⁹, Rachel Schneider ⁹, Jayne Vogelzang ⁹, Karsten Krug ², Amy Goodale ², Tanaz Abid ², Zohra Kalani ², Federica Piccioni ², Rameen Beroukhim ¹ ², Nicole S Persky ², David E Root ², Angel M Carcaboso ¹³, Benjamin L Ebert ² ¹² ¹⁴, Christine Fuller ¹⁵, Ozgun Babur ¹⁶, Mark W Kieran ⁷ ¹⁷, Chris Jones ⁸, Hasmik Keshishian ², Keith L Ligon ⁹, Steven A Carr ², Timothy N Phoenix ¹⁸ ¹⁹, Pratiti Bandopadhayay ²⁰ ²¹ ²²

Affiliations

1 Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02215, USA.
2 Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
3 Harvard Biological and Biomedical Sciences PhD Program, Harvard University, Cambridge, MA, 02138, USA.
4 Department of Radiation Oncology, Duke University, Durham, NC, 27710, USA.
5 Duke Cancer Institute, Duke University, Durham, NC, 27710, USA.
6 The Preston Robert Tisch Brain Tumor Center at Duke, Duke University, Durham, NC, 27710, USA.
7 Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA.
8 Division of Molecular Pathology, Institute of Cancer Research, London, UK.
9 Department of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, 02215, USA.
10 Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45267, USA.
11 Research in Patient Services, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45267, USA.
12 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
13 Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Deu, Institut de Recerca Sant Joan de Deu, Barcelona, 08950, Spain.
14 Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA.
15 Department of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45267, USA.
16 College of Science and Mathematics, University of Massachusetts Boston, Boston, MA, 02125, USA.
17 Bristol Myers Squibb, Boston, Devens, MA, 01434, USA.
18 Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45267, USA. phoenity@ucmail.uc.edu.
19 Research in Patient Services, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45267, USA. phoenity@ucmail.uc.edu.
20 Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. Pratiti_bandopadhayay@dfci.harvard.edu.
21 Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA. Pratiti_bandopadhayay@dfci.harvard.edu.
22 Department of Pediatrics, Harvard Medical School, Boston, MA, 02215, USA. Pratiti_bandopadhayay@dfci.harvard.edu.
# Contributed equally.

PMID: 35105861 DOI: 10.1038/s41467-022-28198-8

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.

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HY-15832

GSK 2830371

99.70%, Wip1 Phosphatase Inhibitor

Phosphatase

Cancer

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