PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation
Por:
Khadka P, Reitman ZJ, Lu S, Buchan G, Gionet G, Dubois F, Carvalho DM, Shih J, Zhang S, Greenwald NF, Zack T, Shapira O, Pelton K, Hartley R, Bear H, Georgis Y, Jarmale S, Melanson R, Bonanno K, Schoolcraft K, Miller PG, Condurat AL, Gonzalez EM, Qian K, Morin E, Langhnoja J, Lupien LE, Rendo V, Digiacomo J, Wang D, Zhou K, Kumbhani R, Guerra Garcia ME, Sinai CE, Becker S, Schneider R, Vogelzang J, Krug K, Goodale A, Abid T, Kalani Z, Piccioni F, Beroukhim R, Persky NS, Root DE, Carcaboso AM, Ebert BL, Fuller C, Babur O, Kieran MW, Jones C, Keshishian H, Ligon KL, Carr SA, Phoenix TN and Bandopadhayay P
Publicada:
1 feb 2022
Resumen:
PPM1D is a known mediator of p53 signalling, and has been linked to treatment resistance in glioma. In this work, the authors utilise genomics, proteomics, and mouse models to determine the role of PPM1D in the development of diffuse midline glioma.
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.
Filiaciones:
Khadka P:
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02215, USA
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Harvard Biological and Biomedical Sciences PhD Program, Harvard University, Cambridge, MA, 02138, USA
Reitman ZJ:
Department of Radiation Oncology, Duke University, Durham, NC, 27710, USA
Duke Cancer Institute, Duke University, Durham, NC, 27710, USA
The Preston Robert Tisch Brain Tumor Center at Duke, Duke University, Durham, NC, 27710, USA
Lu S:
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA
Buchan G:
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA
Gionet G:
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA
Dubois F:
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02215, USA
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Carvalho DM:
Division of Molecular Pathology, Institute of Cancer Research, London, UK
Shih J:
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Zhang S:
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Greenwald NF:
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02215, USA
Zack T:
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02215, USA
Shapira O:
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02215, USA
Pelton K:
Department of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, 02215, USA
Hartley R:
Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45267, USA
Bear H:
Research in Patient Services, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45267, USA
Georgis Y:
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA
Jarmale S:
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA
Melanson R:
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Bonanno K:
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Schoolcraft K:
Department of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, 02215, USA
Miller PG:
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
Condurat AL:
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA
Gonzalez EM:
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA
Qian K:
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA
Morin E:
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA
Langhnoja J:
Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45267, USA
Lupien LE:
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA
Rendo V:
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02215, USA
Digiacomo J:
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA
Wang D:
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA
Zhou K:
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA
Kumbhani R:
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA
Guerra Garcia ME:
Duke Cancer Institute, Duke University, Durham, NC, 27710, USA
Sinai CE:
Department of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, 02215, USA
Becker S:
Department of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, 02215, USA
Schneider R:
Department of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, 02215, USA
Vogelzang J:
Department of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, 02215, USA
Krug K:
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Goodale A:
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Abid T:
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Kalani Z:
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Piccioni F:
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Beroukhim R:
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02215, USA
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Persky NS:
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Root DE:
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Carcaboso AM:
Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Deu, Institut de Recerca Sant Joan de Deu, Barcelona, 08950, Spain
Ebert BL:
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA
Fuller C:
Department of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45267, USA
Babur O:
College of Science and Mathematics, University of Massachusetts Boston, Boston, MA, 02125, USA
Kieran MW:
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA
Bristol Myers Squibb, Boston, Devens, MA, 01434, USA
Jones C:
Division of Molecular Pathology, Institute of Cancer Research, London, UK
Keshishian H:
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Ligon KL:
Department of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, 02215, USA
Carr SA:
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
Phoenix TN:
Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45267, USA.
Research in Patient Services, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45267, USA.
Bandopadhayay P:
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA.
Department of Pediatrics, Harvard Medical School, Boston, MA, 02215, USA.
Green Submitted, gold
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