Upregulation of MYCN Histone H3.3 Mutations Drive Pediatric Glioblastoma through

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 defi ned by highly specifi c 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-specifi c 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. SIGNIFICANCE: We provide the mechanistic explanation for how the fi rst 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); 1–8. ©2013 AACR. Authors’ Affi liations: 1 Divisions of Molecular Pathology and 2 Cancer Therapeutics, and 3 Breakthrough Breast Cancer Research Centre and CRUK Gene Function Laboratory, Division of Breast Cancer Research, The Institute of Cancer Research; 4 Royal Veterinary College; 5 Great Ormond Street Hospital, London, United Kingdom; 6 University of Coimbra, Coimbra; 7 ICVS, University of Minho, Braga, Portugal; and 8 Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos SP, Brazil Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/). Corresponding Author: Chris Jones, Glioma Team, Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG, United Kingdom. Phone: 44-020-8722-4416; Fax: 44-020-8722-4321; E-mail: [email protected] doi: 10.1158/2159-8290.CD-12-0426 ©2013 American Association for Cancer Research. INTRODUCTION The clinical and molecular differences observed in glioblastoma (GBM) of children and young adults compared with the more common, histologically similar lesions in older adults is strongly suggestive of a distinct underlying biology ( 1 ). The identifi cation of unique and highly specifi c mutations in the gene H3F3A , encoding the variant histone H3.3A in GBM of Histone H3.3 Mutations Drive Pediatric Glioblastoma through Upregulation of MYCN Lynn Bjerke 1 , 2 , Alan Mackay 1 , 2 , Meera Nandhabalan 1 , 2 , Anna Burford 1 , 2 , Alexa Jury 1 , 2 , Sergey Popov 1 , 2 , Dorine A. Bax 1 , 2 , Diana Carvalho 1 , 2 , 6 , 7 , Kathryn R. Taylor 1 , 2 , Maria Vinci 1 , 2 , Ilirjana Bajrami 1 , 3 , Imelda M. McGonnell 4 , Christopher J. Lord 1 , 3 , Rui M. Reis 7 , 8 , Darren Hargrave 5 , Alan Ashworth 1 , 3 , Paul Workman 2 , and Chris Jones 1 , 2 on May 14, 2013. © 2013 American Association for Cancer Research. cancerdiscovery.aacrjournals.org Downloaded from Published OnlineFirst March 28, 2013; DOI: 10.1158/2159-8290.CD-12-0426