dc.contributor.author | Sweha, SR | |
dc.contributor.author | Chung, C | |
dc.contributor.author | Natarajan, SK | |
dc.contributor.author | Panwalkar, P | |
dc.contributor.author | Pun, M | |
dc.contributor.author | Ghali, A | |
dc.contributor.author | Bayliss, J | |
dc.contributor.author | Pratt, D | |
dc.contributor.author | Shankar, A | |
dc.contributor.author | Ravikumar, V | |
dc.contributor.author | Rao, A | |
dc.contributor.author | Cieslik, M | |
dc.contributor.author | Wilder-Romans, K | |
dc.contributor.author | Scott, AJ | |
dc.contributor.author | Wahl, DR | |
dc.contributor.author | Jessa, S | |
dc.contributor.author | Kleinman, CL | |
dc.contributor.author | Jabado, N | |
dc.contributor.author | Mackay, A | |
dc.contributor.author | Jones, C | |
dc.contributor.author | Martinez, D | |
dc.contributor.author | Santi, M | |
dc.contributor.author | Judkins, AR | |
dc.contributor.author | Yadav, VN | |
dc.contributor.author | Qin, T | |
dc.contributor.author | Phoenix, TN | |
dc.contributor.author | Koschmann, CJ | |
dc.contributor.author | Baker, SJ | |
dc.contributor.author | Chinnaiyan, AM | |
dc.contributor.author | Venneti, S | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2024-04-15T12:16:13Z | |
dc.date.available | 2024-04-15T12:16:13Z | |
dc.date.issued | 2021-10-13 | |
dc.identifier | ARTN eabf7860 | |
dc.identifier.citation | Science Translational Medicine, 2021, 13 (615), pp. eabf7860 - | |
dc.identifier.issn | 1946-6234 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/6201 | |
dc.identifier.eissn | 1946-6242 | |
dc.identifier.eissn | 1946-6242 | |
dc.identifier.doi | 10.1126/scitranslmed.abf7860 | |
dc.identifier.doi | 10.1126/scitranslmed.abf7860 | |
dc.description.abstract | High-grade gliomas with arginine or valine substitutions of the histone H3.3 glycine-34 residue (H3.3G34R/V) carry a dismal prognosis, and current treatments, including radiotherapy and chemotherapy, are not curative. Because H3.3G34R/V mutations reprogram epigenetic modifications, we undertook a comprehensive epigenetic approach using ChIP sequencing and ChromHMM computational analysis to define therapeutic dependencies in H3.3G34R/V gliomas. Our analyses revealed a convergence of epigenetic alterations, including (i) activating epigenetic modifications on histone H3 lysine (K) residues such as H3K36 trimethylation (H3K36me3), H3K27 acetylation (H3K27ac), and H3K4 trimethylation (H3K4me3); (ii) DNA promoter hypomethylation; and (iii) redistribution of repressive histone H3K27 trimethylation (H3K27me3) to intergenic regions at the leukemia inhibitory factor (LIF) locus to drive increased LIF abundance and secretion by H3.3G34R/V cells. LIF activated signal transducer and activator of transcription 3 (STAT3) signaling in an autocrine/paracrine manner to promote survival of H3.3G34R/V glioma cells. Moreover, immunohistochemistry and single-cell RNA sequencing from H3.3G34R/V patient tumors revealed high STAT3 protein and RNA expression, respectively, in tumor cells with both inter- and intratumor heterogeneity. We targeted STAT3 using a blood-brain barrier–penetrable small-molecule inhibitor, WP1066, currently in clinical trials for adult gliomas. WP1066 treatment resulted in H3.3G34R/V tumor cell toxicity in vitro and tumor suppression in preclinical mouse models established with KNS42 cells, SJ-HGGx42-c cells, or in utero electroporation techniques. Our studies identify the LIF/STAT3 pathway as a key epigenetically driven and druggable vulnerability in H3.3G34R/V gliomas. This finding could inform development of targeted, combination therapies for these lethal brain tumors. | |
dc.format | Print-Electronic | |
dc.format.extent | eabf7860 - | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC ADVANCEMENT SCIENCE | |
dc.relation.ispartof | Science Translational Medicine | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Animals | |
dc.subject | Brain Neoplasms | |
dc.subject | Epigenesis, Genetic | |
dc.subject | Glioma | |
dc.subject | Glycine | |
dc.subject | Histones | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.title | Epigenetically defined therapeutic targeting in H3.3G34R/V high-grade gliomas. | |
dc.type | Journal Article | |
dc.date.updated | 2024-04-11T16:59:14Z | |
rioxxterms.version | AM | |
rioxxterms.versionofrecord | 10.1126/scitranslmed.abf7860 | |
rioxxterms.licenseref.uri | http://creativecommons.org/licenses/by/4.0/ | |
rioxxterms.licenseref.startdate | 2021-10-13 | |
rioxxterms.type | Journal Article/Review | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/34644147 | |
pubs.issue | 615 | |
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 | |
pubs.publisher-url | http://dx.doi.org/10.1126/scitranslmed.abf7860 | |
pubs.volume | 13 | |
icr.researchteam | Glioma Team | |
dc.contributor.icrauthor | Mackay, Alan | |
dc.contributor.icrauthor | Jones, Chris | |
icr.provenance | Deposited by Prof Chris Jones on 2024-04-11. Deposit type is initial. No. of files: 1. Files: Epigenetically defined therapeutic targeting in H3.3G34RV high-grade gliomas.pdf | |