Histone H3.3 Mutations Drive Pediatric Glioblastoma through Upregulation of MYCN
Lynn Bjerke,Alan Mackay,Meera Nandhabalan,Anna Burford,Alexa Jury,Sergey V. Popov,Dorine A. Bax,Diana Carvalho,Diana Carvalho,Kathryn R. Taylor,Maria Vinci,Ilirjana Bajrami,Imelda M. McGonnell,Christopher J. Lord,Rui Manuel Reis,Darren Hargrave,Alan Ashworth,Paul Workman,Chris Jones +18 more
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TLDR
The mechanistic explanation for how the first 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 is provided.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.
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); 512–19. ©2013 AACR .
See related commentary by Huang and Weiss, [p. 484][1]
This article is highlighted in the In This Issue feature, [p. 471][2]
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DNA methylation age of human tissues and cell types
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Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma
Alan Mackay,Anna Burford,Diana Carvalho,Elisa Izquierdo,Janat Fazal-Salom,Kathryn R. Taylor,Kathryn R. Taylor,Lynn Bjerke,Matthew Clarke,Mara Vinci,Meera Nandhabalan,Sara Temelso,Sergey Popov,Sergey Popov,Valeria Molinari,Pichai Raman,Angela J. Waanders,Harry J. Han,Saumya Gupta,Lynley V. Marshall,Stergios Zacharoulis,Sucheta Vaidya,Henry Mandeville,Leslie R. Bridges,Andrew J. Martin,Safa Al-Sarraj,Christopher Chandler,Ho Keung Ng,Xingang Li,Kun Mu,Saoussen Trabelsi,Dorra H'mida-Ben Brahim,Alexei N. Kisljakov,Dmitry M. Konovalov,Andrew S. Moore,Angel M. Carcaboso,Mariona Suñol,Carmen Torres,Ofelia Cruz,Jaume Mora,Ludmila I. Shats,João Norberto Stávale,Lucas Tadeu Bidinotto,Rui Manuel Reis,Natacha Entz-Werle,Michael A. Farrell,Jane Cryan,Darach Crimmins,John Caird,Jane Pears,Michelle Monje,Marie-Anne Debily,David Castel,Jacques Grill,Cynthia Hawkins,Hamid Nikbakht,Nada Jabado,Suzanne J. Baker,Stefan M. Pfister,Stefan M. Pfister,David T.W. Jones,Maryam Fouladi,André O. von Bueren,André O. von Bueren,Michael Baudis,Adam C. Resnick,Chris Jones +66 more
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Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone.
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Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge
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TL;DR: The hallmark genetic alterations that are associated with distinct epigenetic features and patient characteristics in both paediatric and adult disease are summarized, and the complex interplay between the glioblastoma genome and epigenome is examined.
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Understanding the language of Lys36 methylation at histone H3
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Dong Anh Khuong-Quang,Pawel Buczkowicz,Patricia Rakopoulos,Xiaoyang Liu,Adam M. Fontebasso,Eric Bouffet,Ute Bartels,Steffen Albrecht,Jeremy Schwartzentruber,Louis Letourneau,Mathieu Bourgey,Guillaume Bourque,Alexandre Montpetit,Geneviève Bourret,Pierre Lepage,Adam Fleming,Peter Lichter,Marcel Kool,Andreas von Deimling,Dominik Sturm,Andrey Korshunov,Damien Faury,David T.W. Jones,Jacek Majewski,Stefan M. Pfister,Stefan M. Pfister,Nada Jabado,Nada Jabado,Cynthia Hawkins +28 more
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