title: Histone H3.3. mutations drive pediatric glioblastoma through upregulation of MYCN.
abstract: 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.
  
  
  CONCLUSIONS
  We provide the mechanistic explanation for how the fi rst histone gene mutation inhuman 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
authors.affiliation: Divisions of Molecular Pathology and Cancer Therapeutics. The Institute of Cancer Research, Suttonn, Surrey, United Kingdom.
authors.forename: Lynn
authors.initials: L
authors.lastname: Bjerke
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay
authors.forename: Meera
authors.initials: M
authors.lastname: Nandhabalan
authors.forename: Anna
authors.initials: A
authors.lastname: Burford
authors.forename: Alexa
authors.initials: A
authors.lastname: Jury
authors.forename: Sergey
authors.initials: S
authors.lastname: Popov
authors.forename: Dorine A
authors.initials: DA
authors.lastname: Bax
authors.forename: Diana
authors.initials: D
authors.lastname: Carvalho
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Taylor
authors.forename: Maria
authors.initials: M
authors.lastname: Vinci
authors.forename: Ilirjana
authors.initials: I
authors.lastname: Bajrami
authors.forename: Imelda M
authors.initials: IM
authors.lastname: McGonnell
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.forename: Rui M
authors.initials: RM
authors.lastname: Reis
authors.forename: Darren
authors.initials: D
authors.lastname: Hargrave
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
mesh_terms: D000293:Adolescent; D045744:Cell Line, Tumor; D002648:Child; D047369:Chromatin Immunoprecipitation; D016000:Cluster Analysis; D019295:Computational Biology; D004252:DNA Mutational Analysis; D030561:Databases, Nucleic Acid; D066264:Datasets as Topic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009154:Mutation; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D006657:Histones; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins
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