Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis.
Animals
Astrocytes
/ metabolism
Brain Neoplasms
/ genetics
Carcinogenesis
/ genetics
Cell Lineage
Cellular Reprogramming
/ genetics
Chromatin
/ metabolism
Embryo, Mammalian
/ metabolism
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic
Gene Silencing
Glioma
/ genetics
Histones
/ genetics
Interneurons
/ metabolism
Lysine
/ metabolism
Mice, Inbred C57BL
Models, Biological
Mutation
/ genetics
Neoplasm Grading
Neural Stem Cells
/ metabolism
Oligodendroglia
/ metabolism
Promoter Regions, Genetic
/ genetics
Prosencephalon
/ embryology
Receptor, Platelet-Derived Growth Factor alpha
/ genetics
Transcription, Genetic
Transcriptome
/ genetics
GSX2
H3.3 G34R/V
PDGFRA
cell-of-origin
chromatin conformation
gliomas
interneuron progenitors
oncohistones
pediatric cancer
single-cell transcriptome
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
10 12 2020
10 12 2020
Historique:
received:
29
07
2020
revised:
01
10
2020
accepted:
06
11
2020
pubmed:
2
12
2020
medline:
19
5
2021
entrez:
1
12
2020
Statut:
ppublish
Résumé
Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.
Identifiants
pubmed: 33259802
pii: S0092-8674(20)31529-4
doi: 10.1016/j.cell.2020.11.012
pmc: PMC7791404
mid: NIHMS1656227
pii:
doi:
Substances chimiques
Chromatin
0
Histones
0
Receptor, Platelet-Derived Growth Factor alpha
EC 2.7.10.1
Lysine
K3Z4F929H6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1617-1633.e22Subventions
Organisme : CIHR
ID : PJT-156086
Pays : Canada
Organisme : CIHR
ID : FDN-154307
Pays : Canada
Organisme : NCRR NIH HHS
ID : P41 RR000862
Pays : United States
Organisme : CIHR
ID : MOP-286756
Pays : Canada
Organisme : Medical Research Council
ID : MR/M00094X/1
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R00 CA201592
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA219943
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA165962
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA196539
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA159859
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA215489
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA148699
Pays : United States
Informations de copyright
Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests P.B. and R.B. receive grant funding from the Novartis Institute of Biomedical Research for an unrelated project. J.R.H. has received compensation for consultation from Bayer for unrelated work.
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