ArticleNature communications2022
PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation.
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Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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37citing papers in PubMed
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Who cites it
37 citing papers in PubMed, 53 citations in OpenAlex.
- Targeted therapies plus radiotherapy for diffuse intrinsic pontine glioma: the randomized phase 2 BIOMEDE trial.Nature medicine · 2026Trial
- Understanding DMG: current treatment options and prospective solutions using nanoparticles.Drug delivery and translational research · 2026Review
- Combined inhibition of PLK4 and PPM1D promotes cell death in cancer cells with 17q amplification.Cancer cell international · 2026Article
- Delivery of ATSP-7041 by Minimally Invasive Nasal Depot (MIND) to Target Diffuse Intrinsic Pontine Glioma.Molecular cancer therapeutics · 2026Article
- Diffuse Midline Gliomas: Clinical, Diagnostic, and Therapeutic Perspectives.Biomedicines · 2026Review
- OncogenicbioRxiv : the preprint server for biology · 2025Article
- Analysis and Interpretation of Somatic NMD-Escaping Variants in Oncogenes and Dual-Function Genes across Adult and Pediatric Cancer Cohorts.medRxiv : the preprint server for health sciences · 2025Article
- Proteomic sensors for quantitative multiplexed and spatial monitoring of kinase signaling.Nature communications · 2025Article
- Article
- Gain-of-function PPM1D mutations attenuate ischemic stroke.Cell death and differentiation · 2025Article
- PPM1D is directly degraded by proteasomes in a ubiquitination-independent manner through its carboxyl-terminal region.Journal of biomedical science · 2025Article
- Current Landscape of Preclinical Models for Pediatric Gliomas: Clinical Implications and Future Directions.Cancers · 2025Review
- An ATM-PPM1D Circuit Controls the Processing and Restart of DNA Replication Forks.bioRxiv : the preprint server for biology · 2025Article
- Establishment of xenografts and methods to evaluate tumor burden for the three most frequent subclasses of pediatric-type diffuse high grade gliomas.Journal of neuro-oncology · 2025Article
- Identification of small molecule inhibitors of PPM1D using an integrated drug discovery platform.iScience · 2025Article
- PPM1D activity promotes cellular transformation by preventing senescence and cell death.Oncogene · 2024Article
- Review
- Primary thyroid nuclear protein in testis carcinoma: a case report and literature review.Gland surgery · 2024Article
- Article
- The Landscape of Pediatric High-Grade Gliomas: The Virtues and Pitfalls of Pre-Clinical Models.Biology · 2024Review
Corrections and comments
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Authors and funding
56 authors at 10 institutions in 4 countries.
Prasidda Khadka *Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02215, USA.ORCID http://orcid.org/0000-0002-3732-7600
Zachary J Reitman *Department of Radiation Oncology, Duke University, Durham, NC, 27710, USA.
Sophie LuDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA.
Graham BuchanDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA.
Gabrielle GionetDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA.
Frank DuboisDepartment of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02215, USA.
Diana M CarvalhoDivision of Molecular Pathology, Institute of Cancer Research, London, UK.ORCID http://orcid.org/0000-0001-6881-6151
Juliann ShihBroad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.ORCID http://orcid.org/0000-0002-4086-8651
Shu ZhangBroad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Noah F GreenwaldDepartment of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02215, USA.
Travis ZackDepartment of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02215, USA.
Ofer ShapiraDepartment of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02215, USA.
Kristine PeltonDepartment of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, 02215, USA.
Rachel HartleyDivision of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45267, USA.
Heather BearResearch in Patient Services, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45267, USA.
Yohanna GeorgisDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA.
Spandana JarmaleDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA.
Randy MelansonBroad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Kevin BonannoBroad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Kathleen SchoolcraftDepartment of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, 02215, USA.
Peter G MillerBroad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Alexandra L ConduratDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA.
Elizabeth M GonzalezBroad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Kenin QianDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA.
Eric MorinDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA.ORCID http://orcid.org/0000-0002-0578-4516
Jaldeep LanghnojaDivision of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45267, USA.
Leslie E LupienDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA.
Veronica RendoDepartment of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02215, USA.
Jeromy DigiacomoDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA.
Dayle WangDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA.ORCID http://orcid.org/0000-0002-2185-1782
Kevin ZhouDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA.ORCID http://orcid.org/0000-0003-1567-3606
Rushil KumbhaniDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA.
Maria E Guerra GarciaDuke Cancer Institute, Duke University, Durham, NC, 27710, USA.
Claire E SinaiDepartment of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, 02215, USA.
Sarah BeckerDepartment of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, 02215, USA.
Rachel SchneiderDepartment of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, 02215, USA.
Jayne VogelzangDepartment of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, 02215, USA.
Karsten KrugBroad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Amy GoodaleBroad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Tanaz AbidBroad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Zohra KalaniBroad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Federica PiccioniBroad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.ORCID http://orcid.org/0000-0003-1210-3210
Rameen BeroukhimDepartment of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, 02215, USA.ORCID http://orcid.org/0000-0001-6303-3609
Nicole S PerskyBroad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
David E RootBroad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.ORCID http://orcid.org/0000-0001-5122-861X
Angel M CarcabosoDepartment of Pediatric Hematology and Oncology, Hospital Sant Joan de Deu, Institut de Recerca Sant Joan de Deu, Barcelona, 08950, Spain.ORCID http://orcid.org/0000-0002-8485-426X
Benjamin L EbertBroad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.ORCID http://orcid.org/0000-0003-0197-5451
Christine FullerDepartment of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45267, USA.
Ozgun BaburCollege of Science and Mathematics, University of Massachusetts Boston, Boston, MA, 02125, USA.
Mark W KieranDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, 02215, USA.
Chris JonesDivision of Molecular Pathology, Institute of Cancer Research, London, UK.
Hasmik KeshishianBroad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Keith L LigonDepartment of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, 02215, USA.
Steven A CarrBroad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Timothy N PhoenixDivision of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, 45267, USA. phoenity@ucmail.uc.edu.ORCID http://orcid.org/0000-0003-4771-4003
Pratiti BandopadhayayBroad Institute of MIT and Harvard, Cambridge, MA, 02142, USA. Pratiti_bandopadhayay@dfci.harvard.edu.
Broad Institute · USDana-Farber/Boston Children's Cancer and Blood Disorders Center · USDana-Farber Cancer Institute · USCincinnati Children's Hospital Medical Center · USDuke University · USInstitute of Cancer Research · GBUniversity of Cincinnati Medical Center · USBristol-Myers Squibb (Germany) · DEHospital Sant Joan de Déu Barcelona · ESUniversity of Massachusetts Boston · US
Funding
Women's Cancer Research ProgramP30CA014236 · NCI · DUKE UNIVERSITY · PI JOHN N. NORTON · 1985 to 2026
$174.8MMICROSCALED PROTEOGENOMICS FOR CANCER CLINICAL TRIALSU01CA214125 · NCI · BAYLOR COLLEGE OF MEDICINE · PI ANURAG, MEENAKSHI, CARR, STEVEN A · 2017 to 2021
$7.0MGenetic evolution of glioblastomas during radiation and temozolomide therapyR01CA188228 · NCI · DANA-FARBER CANCER INST · PI BEROUKHIM, RAMEEN, CHAKRAVARTI, ARNAB · 2015 to 2025
$6.9MCenter of Excellence for High Throughput Proteogenomic CharacterizationU24CA210986 · NCI · BROAD INSTITUTE, INC. · PI CARR, STEVEN A, GILLETTE, MICHAEL A · 2016 to 2020
$6.4MMYB family alterations in pediatric gliomasR01CA215489 · NCI · DANA-FARBER CANCER INST · PI BEROUKHIM, RAMEEN, LIGON, KEITH LLOYD · 2017 to 2021
$2.8MCharacterizing TP53 and PPM1D mutations as resistance drivers to radiation therapy in Diffuse Intrinsic Pontine GliomasR01CA219943 · NCI · BROAD INSTITUTE, INC. · PI BEROUKHIM, RAMEEN, LIGON, KEITH LLOYD · 2017 to 2021
$2.5MTargeting vulnerabilities of PPM1D-mutant gliomasR37CA255245 · NCI · DANA-FARBER CANCER INST · PI Pratiti Bandopadhayay · 2021 to 2026
$2.4MRole of PPM1D and PPM1D mutations in hematopoiesis and response to stressK08CA263183 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI MILLER, PETER GRANT · 2021 to 2025
$1.1MCharacterizing the resistance mechanisms to BET-bromodomain inhibition in MYC-amplified medulloblastomaR00CA201592 · NCI · DANA-FARBER CANCER INST · PI BANDOPADHAYAY, PRATITI · 2018 to 2020
$697kCancer Research UK 13982Cancer Research UK 23536NCI NIH HHS R00 CA201592NCI NIH HHS R01 CA188228NCI NIH HHS R01 CA215489NCI NIH HHS R01 CA219943NCI NIH HHS R37 CA255245NCI NIH HHS U01 CA214125NCI NIH HHS U24 CA210986
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.
Indexed as
MutationAdolescentAdultAnimalsBrain Stem NeoplasmsCarcinogenesisCell CycleChildChild, PreschoolDisease Models, AnimalDNA DamageFemaleGliomaHEK293 CellsHumansInfantPPM1D protein, humanProtein Phosphatase 2CProto-Oncogene Proteins c-mdm2Tumor Suppressor Protein p53
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