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TitleHistone H3.3 mutations drive pediatric glioblastoma through upregulation of MYCN
Mackay, Alan
Nandhabalan, Meera
Burford, Anna
Jury, Alexa
Popov, Sergey
Bax, Dorine A.
Carvalho, Diana
Taylor, Kathryn R.
Vinci, Maria
Bajrami, Ilirjana
McGonnell, Imelda M.
Reis, R. M.
Hargrave, Darren
Ashworth, Alan
Workman, Paul
Advisor(s)Chris Jones
Issue date1-Apr-2013
PublisherAmerican Association for Cancer Research
JournalCancer Discovery
Abstract(s)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-K27 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.
Publisher version
AccessOpen access
Appears in Collections:ICVS - Artigos em Revistas Internacionais com Referee

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