dc.contributor.author | Fons, NR | |
dc.contributor.author | Sundaram, RK | |
dc.contributor.author | Breuer, GA | |
dc.contributor.author | Peng, S | |
dc.contributor.author | McLean, RL | |
dc.contributor.author | Kalathil, AN | |
dc.contributor.author | Schmidt, MS | |
dc.contributor.author | Carvalho, DM | |
dc.contributor.author | Mackay, A | |
dc.contributor.author | Jones, C | |
dc.contributor.author | Carcaboso, ÁM | |
dc.contributor.author | Nazarian, J | |
dc.contributor.author | Berens, ME | |
dc.contributor.author | Brenner, C | |
dc.contributor.author | Bindra, RS | |
dc.coverage.spatial | England | |
dc.date.accessioned | 2022-11-23T09:12:35Z | |
dc.date.available | 2022-11-23T09:12:35Z | |
dc.date.issued | 2019-08-22 | |
dc.identifier | ARTN 3790 | |
dc.identifier | 10.1038/s41467-019-11732-6 | |
dc.identifier.citation | Nature Communications, 2019, 10 (1), pp. 3790 - | |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5567 | |
dc.identifier.eissn | 2041-1723 | |
dc.identifier.eissn | 2041-1723 | |
dc.identifier.doi | 10.1038/s41467-019-11732-6 | |
dc.description.abstract | Pediatric 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.format | Electronic | |
dc.format.extent | 3790 - | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE RESEARCH | |
dc.relation.ispartof | Nature Communications | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Animals | |
dc.subject | Antineoplastic Agents | |
dc.subject | Brain Stem Neoplasms | |
dc.subject | Cell Line, Tumor | |
dc.subject | Child | |
dc.subject | Cytokines | |
dc.subject | DNA Methylation | |
dc.subject | Diffuse Intrinsic Pontine Glioma | |
dc.subject | Epigenetic Repression | |
dc.subject | Female | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Nicotinamide Phosphoribosyltransferase | |
dc.subject | Pons | |
dc.subject | Primary Cell Culture | |
dc.subject | Protein Phosphatase 2C | |
dc.subject | Synthetic Lethal Mutations | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.title | PPM1D mutations silence NAPRT gene expression and confer NAMPT inhibitor sensitivity in glioma. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2019-08-01 | |
dc.date.updated | 2022-11-21T08:51:18Z | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1038/s41467-019-11732-6 | |
rioxxterms.licenseref.startdate | 2019-08-22 | |
rioxxterms.type | Journal Article/Review | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/31439867 | |
pubs.issue | 1 | |
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-status | Published online | |
pubs.publisher-url | http://dx.doi.org/10.1038/s41467-019-11732-6 | |
pubs.volume | 10 | |
icr.researchteam | Glioma Team | |
dc.contributor.icrauthor | Mackay, Alan | |
dc.contributor.icrauthor | Jones, Chris | |
icr.provenance | Deposited 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 | |