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Cancer Cell. 2017 Nov 13;32(5):684-700.e9. doi: 10.1016/j.ccell.2017.09.014. Epub 2017 Oct 26.

H3.3K27M Cooperates with Trp53 Loss and PDGFRA Gain in Mouse Embryonic Neural Progenitor Cells to Induce Invasive High-Grade Gliomas.

Author information

1
Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London WC1E 6DD, UK.
2
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.
3
MRC Laboratory for Molecular Cell Biology, UCL, London WC1E 6BT, UK.
4
Nuclear Function Group, German Centre for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Straße 27, Bonn 53127, Germany.
5
Bill Lyons Informatics Centre, UCL Cancer Institute, London WC1E 6DD, UK.
6
UCL Institute of Neurology, London WC1N 3BG, UK.
7
The Lady Davis Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
8
Department of Pathology, McGill University, Montreal, QC H3A 2B4, Canada.
9
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; The Lady Davis Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.
10
Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada; Department of Pediatrics, McGill University, Montreal, QC H4A 3J1, Canada. Electronic address: nada.jabado@mcgill.ca.
11
Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London WC1E 6DD, UK; Nuclear Function Group, German Centre for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Straße 27, Bonn 53127, Germany. Electronic address: p.salomoni@ucl.ac.uk.

Abstract

Gain-of-function mutations in histone 3 (H3) variants are found in a substantial proportion of pediatric high-grade gliomas (pHGG), often in association with TP53 loss and platelet-derived growth factor receptor alpha (PDGFRA) amplification. Here, we describe a somatic mouse model wherein H3.3K27M and Trp53 loss alone are sufficient for neoplastic transformation if introduced in utero. H3.3K27M-driven lesions are clonal, H3K27me3 depleted, Olig2 positive, highly proliferative, and diffusely spreading, thus recapitulating hallmark molecular and histopathological features of pHGG. Addition of wild-type PDGFRA decreases latency and increases tumor invasion, while ATRX knockdown is associated with more circumscribed tumors. H3.3K27M-tumor cells serially engraft in recipient mice, and preliminary drug screening reveals mutation-specific vulnerabilities. Overall, we provide a faithful H3.3K27M-pHGG model which enables insights into oncohistone pathogenesis and investigation of future therapies.

KEYWORDS:

clonal; mosaic; neurodevelopment; oncohistone; pediatric high-grade glioma

PMID:
29107533
PMCID:
PMC5687892
DOI:
10.1016/j.ccell.2017.09.014
[Indexed for MEDLINE]
Free PMC Article

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