{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T04:23:40Z","timestamp":1775190220210,"version":"3.50.1"},"reference-count":25,"publisher":"American Association for Cancer Research (AACR)","issue":"5","content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Children and young adults with glioblastoma (GBM) have a median survival rate of only 12 to 15 months, and these GBMs are clinically and biologically distinct from histologically similar cancers in older adults. They are defined by highly specific mutations in the gene encoding the histone H3.3 variant H3F3A, occurring either at or close to key residues marked by methylation for regulation of transcription\u2014K27 and G34. Here, we show that the cerebral hemisphere-specific G34 mutation drives a distinct expression signature through differential genomic binding of the K36 trimethylation mark (H3K36me3). The transcriptional program induced recapitulates that of the developing forebrain, and involves numerous markers of stem-cell maintenance, cell-fate decisions, and self-renewal. Critically, H3F3A G34 mutations cause profound upregulation of MYCN, a potent oncogene that is causative of GBMs when expressed in the correct developmental context. This driving aberration is selectively targetable in this patient population through inhibiting kinases responsible for stabilization of the protein.<\/jats:p>\n                  <jats:p>Significance: We provide the mechanistic explanation for how the first histone gene mutation in human disease biology acts to deliver MYCN, a potent tumorigenic initiator, into a stem-cell compartment of the developing forebrain, selectively giving rise to incurable cerebral hemispheric GBM. Using synthetic lethal approaches to these mutant tumor cells provides a rational way to develop novel and highly selective treatment strategies. Cancer Discov; 3(5); 512\u201319. \u00a92013 AACR.<\/jats:p>\n                  <jats:p>See related commentary by Huang and Weiss, p. 484<\/jats:p>\n                  <jats:p>This article is highlighted in the In This Issue feature, p. 471<\/jats:p>","DOI":"10.1158\/2159-8290.cd-12-0426","type":"journal-article","created":{"date-parts":[[2013,3,29]],"date-time":"2013-03-29T00:16:41Z","timestamp":1364516201000},"page":"512-519","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":272,"title":["Histone H3.3 Mutations Drive Pediatric Glioblastoma through Upregulation of MYCN"],"prefix":"10.1158","volume":"3","author":[{"given":"Lynn","family":"Bjerke","sequence":"first","affiliation":[{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"},{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"}]},{"given":"Alan","family":"Mackay","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"},{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"}]},{"given":"Meera","family":"Nandhabalan","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"},{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"}]},{"given":"Anna","family":"Burford","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"},{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"}]},{"given":"Alexa","family":"Jury","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"},{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"}]},{"given":"Sergey","family":"Popov","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"},{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"}]},{"given":"Dorine A.","family":"Bax","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"},{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"}]},{"given":"Diana","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"},{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"},{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"},{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"}]},{"given":"Kathryn R.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"},{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"}]},{"given":"Maria","family":"Vinci","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"},{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"}]},{"given":"Ilirjana","family":"Bajrami","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"},{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"}]},{"given":"Imelda M.","family":"McGonnell","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"}]},{"given":"Christopher J.","family":"Lord","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"},{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast 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Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"}]},{"given":"Darren","family":"Hargrave","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"}]},{"given":"Alan","family":"Ashworth","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"},{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"}]},{"given":"Paul","family":"Workman","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"}]},{"given":"Chris","family":"Jones","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"},{"name":"Authors' Affiliations:\u20081Divisions of Molecular Pathology and 2Cancer Therapeutics, and 3Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4Royal Veterinary College; 5Great Ormond Street Hospital, London, United Kingdom; 6University of Coimbra, Coimbra; 7ICVS, University of Minho, Braga, Portugal; and 8Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil"}]}],"member":"1086","published-online":{"date-parts":[[2013,5,8]]},"reference":[{"key":"2022060623015026100_bib1","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/nrclinonc.2012.87","article-title":"Paediatric and adult malignant glioma: close 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