Full metadata record
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Sweha, Stefan R. | - |
dc.contributor.author | Chung, Chan | - |
dc.contributor.author | Natarajan, Siva Kumar | - |
dc.contributor.author | Panwalkar, Pooja | - |
dc.contributor.author | Pun, Matthew | - |
dc.contributor.author | Ghali, Amer | - |
dc.contributor.author | Bayliss, Jill | - |
dc.contributor.author | Pratt, Drew | - |
dc.contributor.author | Shankar, Anand | - |
dc.contributor.author | Ravikumar, Visweswaran | - |
dc.contributor.author | Rao, Arvind | - |
dc.contributor.author | Cieslik, Marcin | - |
dc.contributor.author | Wilder-Romans, Kari | - |
dc.contributor.author | Scott, Andrew J. | - |
dc.contributor.author | Wahl, Daniel R. | - |
dc.contributor.author | Jessa, Selin | - |
dc.contributor.author | Kleinman, Claudia L. | - |
dc.contributor.author | Jabado, Nada | - |
dc.contributor.author | Mackay, Alan | - |
dc.contributor.author | Jones, Chris | - |
dc.contributor.author | Martinez, Daniel | - |
dc.contributor.author | Santi, Mariarita | - |
dc.contributor.author | Judkins, Alexander R. | - |
dc.contributor.author | Yadav, Viveka Nand | - |
dc.contributor.author | Qin, Tingting | - |
dc.contributor.author | Phoenix, Timothy N. | - |
dc.contributor.author | Koschmann, Carl J. | - |
dc.contributor.author | Baker, Suzanne J. | - |
dc.contributor.author | Chinnaiyan, Arul M. | - |
dc.contributor.author | Venneti, Sriram | - |
dc.date.accessioned | 2021-11-05T07:00:05Z | - |
dc.date.available | 2021-11-05T07:00:05Z | - |
dc.date.created | 2021-10-28 | - |
dc.date.issued | 2021-10 | - |
dc.identifier.citation | Science Translational Medicine, v.13, no.615 | - |
dc.identifier.issn | 1946-6234 | - |
dc.identifier.uri | http://hdl.handle.net/20.500.11750/15756 | - |
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.language | English | - |
dc.publisher | American Association for the Advancement of Science | - |
dc.title | Epigenetically defined therapeutic targeting in H3.3G34R/V high-grade gliomas | - |
dc.type | Article | - |
dc.identifier.doi | 10.1126/scitranslmed.abf7860 | - |
dc.identifier.wosid | 000707525800004 | - |
dc.identifier.scopusid | 2-s2.0-85118514930 | - |
dc.type.local | Article(Overseas) | - |
dc.type.rims | ART | - |
dc.description.journalClass | 1 | - |
dc.citation.publicationname | Science Translational Medicine | - |
dc.contributor.nonIdAuthor | Sweha, Stefan R. | - |
dc.contributor.nonIdAuthor | Natarajan, Siva Kumar | - |
dc.contributor.nonIdAuthor | Panwalkar, Pooja | - |
dc.contributor.nonIdAuthor | Pun, Matthew | - |
dc.contributor.nonIdAuthor | Ghali, Amer | - |
dc.contributor.nonIdAuthor | Bayliss, Jill | - |
dc.contributor.nonIdAuthor | Pratt, Drew | - |
dc.contributor.nonIdAuthor | Shankar, Anand | - |
dc.contributor.nonIdAuthor | Ravikumar, Visweswaran | - |
dc.contributor.nonIdAuthor | Rao, Arvind | - |
dc.contributor.nonIdAuthor | Cieslik, Marcin | - |
dc.contributor.nonIdAuthor | Wilder-Romans, Kari | - |
dc.contributor.nonIdAuthor | Scott, Andrew J. | - |
dc.contributor.nonIdAuthor | Wahl, Daniel R. | - |
dc.contributor.nonIdAuthor | Jessa, Selin | - |
dc.contributor.nonIdAuthor | Kleinman, Claudia L. | - |
dc.contributor.nonIdAuthor | Jabado, Nada | - |
dc.contributor.nonIdAuthor | Mackay, Alan | - |
dc.contributor.nonIdAuthor | Jones, Chris | - |
dc.contributor.nonIdAuthor | Martinez, Daniel | - |
dc.contributor.nonIdAuthor | Santi, Mariarita | - |
dc.contributor.nonIdAuthor | Judkins, Alexander R. | - |
dc.contributor.nonIdAuthor | Yadav, Viveka Nand | - |
dc.contributor.nonIdAuthor | Qin, Tingting | - |
dc.contributor.nonIdAuthor | Phoenix, Timothy N. | - |
dc.contributor.nonIdAuthor | Koschmann, Carl J. | - |
dc.contributor.nonIdAuthor | Baker, Suzanne J. | - |
dc.contributor.nonIdAuthor | Chinnaiyan, Arul M. | - |
dc.contributor.nonIdAuthor | Venneti, Sriram | - |
dc.identifier.citationVolume | 13 | - |
dc.identifier.citationNumber | 615 | - |
dc.identifier.citationTitle | Science Translational Medicine | - |
dc.description.isOpenAccess | Y | - |
dc.subject.keywordPlus | CHROMATIN-STATE DISCOVERY | - |
dc.subject.keywordPlus | CENTRAL-NERVOUS-SYSTEM | - |
dc.subject.keywordPlus | PEDIATRIC HIGH-GRADE | - |
dc.subject.keywordPlus | SIGNAL TRANSDUCERS | - |
dc.subject.keywordPlus | PRC2 ACTIVITY | - |
dc.subject.keywordPlus | MUTATIONS | - |
dc.subject.keywordPlus | INHIBITOR | - |
dc.subject.keywordPlus | METHYLATION | - |
dc.subject.keywordPlus | PHOSPHORYLATION | - |
dc.subject.keywordPlus | PROGENITORS | - |
dc.contributor.affiliatedAuthor | Sweha, Stefan R. | - |
dc.contributor.affiliatedAuthor | Chung, Chan | - |
dc.contributor.affiliatedAuthor | Natarajan, Siva Kumar | - |
dc.contributor.affiliatedAuthor | Panwalkar, Pooja | - |
dc.contributor.affiliatedAuthor | Pun, Matthew | - |
dc.contributor.affiliatedAuthor | Ghali, Amer | - |
dc.contributor.affiliatedAuthor | Bayliss, Jill | - |
dc.contributor.affiliatedAuthor | Pratt, Drew | - |
dc.contributor.affiliatedAuthor | Shankar, Anand | - |
dc.contributor.affiliatedAuthor | Ravikumar, Visweswaran | - |
dc.contributor.affiliatedAuthor | Rao, Arvind | - |
dc.contributor.affiliatedAuthor | Cieslik, Marcin | - |
dc.contributor.affiliatedAuthor | Wilder-Romans, Kari | - |
dc.contributor.affiliatedAuthor | Scott, Andrew J. | - |
dc.contributor.affiliatedAuthor | Wahl, Daniel R. | - |
dc.contributor.affiliatedAuthor | Jessa, Selin | - |
dc.contributor.affiliatedAuthor | Kleinman, Claudia L. | - |
dc.contributor.affiliatedAuthor | Jabado, Nada | - |
dc.contributor.affiliatedAuthor | Mackay, Alan | - |
dc.contributor.affiliatedAuthor | Jones, Chris | - |
dc.contributor.affiliatedAuthor | Martinez, Daniel | - |
dc.contributor.affiliatedAuthor | Santi, Mariarita | - |
dc.contributor.affiliatedAuthor | Judkins, Alexander R. | - |
dc.contributor.affiliatedAuthor | Yadav, Viveka Nand | - |
dc.contributor.affiliatedAuthor | Qin, Tingting | - |
dc.contributor.affiliatedAuthor | Phoenix, Timothy N. | - |
dc.contributor.affiliatedAuthor | Koschmann, Carl J. | - |
dc.contributor.affiliatedAuthor | Baker, Suzanne J. | - |
dc.contributor.affiliatedAuthor | Chinnaiyan, Arul M. | - |
dc.contributor.affiliatedAuthor | Venneti, Sriram | - |
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