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dc.contributor.authorFons, NR
dc.contributor.authorSundaram, RK
dc.contributor.authorBreuer, GA
dc.contributor.authorPeng, S
dc.contributor.authorMcLean, RL
dc.contributor.authorKalathil, AN
dc.contributor.authorSchmidt, MS
dc.contributor.authorCarvalho, DM
dc.contributor.authorMackay, A
dc.contributor.authorJones, C
dc.contributor.authorCarcaboso, ÁM
dc.contributor.authorNazarian, J
dc.contributor.authorBerens, ME
dc.contributor.authorBrenner, C
dc.contributor.authorBindra, RS
dc.coverage.spatialEngland
dc.date.accessioned2022-11-23T09:12:35Z
dc.date.available2022-11-23T09:12:35Z
dc.date.issued2019-08-22
dc.identifierARTN 3790
dc.identifier10.1038/s41467-019-11732-6
dc.identifier.citationNature Communications, 2019, 10 (1), pp. 3790 -en_US
dc.identifier.issn2041-1723
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5567
dc.identifier.eissn2041-1723
dc.identifier.eissn2041-1723
dc.identifier.doi10.1038/s41467-019-11732-6
dc.identifier.doi10.1038/s41467-019-11732-6
dc.description.abstractPediatric high-grade gliomas are among the deadliest of childhood cancers due to limited knowledge of early driving events in their gliomagenesis and the lack of effective therapies available. In this study, we investigate the oncogenic role of PPM1D, a protein phosphatase often found truncated in pediatric gliomas such as DIPG, and uncover a synthetic lethal interaction between PPM1D mutations and nicotinamide phosphoribosyltransferase (NAMPT) inhibition. Specifically, we show that mutant PPM1D drives hypermethylation of CpG islands throughout the genome and promotes epigenetic silencing of nicotinic acid phosphoribosyltransferase (NAPRT), a key gene involved in NAD biosynthesis. Notably, PPM1D mutant cells are shown to be sensitive to NAMPT inhibitors in vitro and in vivo, within both engineered isogenic astrocytes and primary patient-derived model systems, suggesting the possible application of NAMPT inhibitors for the treatment of pediatric gliomas. Overall, our results reveal a promising approach for the targeting of PPM1D mutant tumors, and define a critical link between oncogenic driver mutations and NAD metabolism, which can be exploited for tumor-specific cell killing.
dc.formatElectronic
dc.format.extent3790 -
dc.languageeng
dc.language.isoengen_US
dc.publisherNATURE RESEARCHen_US
dc.relation.ispartofNature Communications
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectAnimals
dc.subjectAntineoplastic Agents
dc.subjectBrain Stem Neoplasms
dc.subjectCell Line, Tumor
dc.subjectChild
dc.subjectCytokines
dc.subjectDNA Methylation
dc.subjectDiffuse Intrinsic Pontine Glioma
dc.subjectEpigenetic Repression
dc.subjectFemale
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectHumans
dc.subjectMice
dc.subjectNicotinamide Phosphoribosyltransferase
dc.subjectPons
dc.subjectPrimary Cell Culture
dc.subjectProtein Phosphatase 2C
dc.subjectSynthetic Lethal Mutations
dc.subjectXenograft Model Antitumor Assays
dc.titlePPM1D mutations silence NAPRT gene expression and confer NAMPT inhibitor sensitivity in glioma.en_US
dc.typeJournal Article
dcterms.dateAccepted2019-08-01
dc.date.updated2022-11-21T08:51:18Z
rioxxterms.versionVoRen_US
rioxxterms.versionofrecord10.1038/s41467-019-11732-6en_US
rioxxterms.licenseref.startdate2019-08-22
rioxxterms.typeJournal Article/Reviewen_US
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/31439867
pubs.issue1
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Glioma Team
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Glioma Team
pubs.publication-statusPublished online
pubs.publisher-urlhttp://dx.doi.org/10.1038/s41467-019-11732-6
pubs.volume10
icr.researchteamGlioma Teamen_US
dc.contributor.icrauthorMackay, Alan
dc.contributor.icrauthorJones, Chris
icr.provenanceDeposited by Dr Diana Martins Carvalho on 2022-11-21. Deposit type is initial. No. of files: 1. Files: PPM1D mutations silence NAPRT gene expression and confer NAMPT inhibitor sensitivity in glioma.pdf


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