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Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis
CCL. Chen, S. Deshmukh, S. Jessa, D. Hadjadj, V. Lisi, AF. Andrade, D. Faury, W. Jawhar, R. Dali, H. Suzuki, M. Pathania, D. A, F. Dubois, E. Woodward, S. Hébert, M. Coutelier, J. Karamchandani, S. Albrecht, S. Brandner, N. De Jay, T. Gayden, A....
Language English Country United States
Document type 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.
Grant support
PJT-156086
CIHR - Canada
FDN-154307
CIHR - Canada
P41 RR000862
NCRR NIH HHS - United States
MOP-286756
CIHR - Canada
R01 CA219943
NCI NIH HHS - United States
P50 CA165962
NCI NIH HHS - United States
P01 CA196539
NCI NIH HHS - United States
R01 CA159859
NCI NIH HHS - United States
R01 CA215489
NCI NIH HHS - United States
R01 CA148699
NCI NIH HHS - United States
MR/M00094X/1
Medical Research Council - United Kingdom
R00 CA201592
NCI NIH HHS - United States
NLK
Cell Press Free Archives
from 1995-01-01 to 1 year ago
Free Medical Journals
from 1995 to 1 year ago
Open Access Digital Library
from 1995-01-01
- MeSH
- Astrocytes metabolism pathology MeSH
- Models, Biological MeSH
- Cell Lineage MeSH
- Chromatin metabolism MeSH
- Embryo, Mammalian metabolism MeSH
- Epigenesis, Genetic MeSH
- Transcription, Genetic MeSH
- Glioma genetics pathology MeSH
- Histones genetics metabolism MeSH
- Interneurons metabolism MeSH
- Carcinogenesis genetics pathology MeSH
- Lysine metabolism MeSH
- Mutation genetics MeSH
- Mice, Inbred C57BL MeSH
- Brain Neoplasms genetics pathology MeSH
- Neural Stem Cells metabolism MeSH
- Oligodendroglia metabolism MeSH
- Prosencephalon embryology MeSH
- Cellular Reprogramming genetics MeSH
- Promoter Regions, Genetic genetics MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Receptor, Platelet-Derived Growth Factor alpha genetics metabolism MeSH
- Neoplasm Grading MeSH
- Transcriptome genetics MeSH
- Gene Silencing MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
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.
2nd Department of Paediatrics Semmelweis University Budapest 1094 Hungary
Broad Institute of MIT and Harvard Boston MA 02142 USA
Canadian Centre for Computational Genomics McGill University Montreal QC H3A 0E9 Canada
Children's Cancer Center The Royal Children's Hospital
Clinical Cooperation Unit Neuropathology German Cancer Consortium Heidelberg 69120 Germany
CRUK Children's Brain Tumour Centre of Excellence University of Cambridge Cambridge CB2 0RE UK
Dana Farber Boston Children's Cancer and Blood Disorders Center Boston MA 02215 USA
Department of Biochemistry McGill University Montreal QC H3A 1A3 Canada
Department of Human Genetics McGill University Montreal QC H3A 0C7 Canada
Department of Medical Oncology Dana Farber Cancer Institute Boston MA 02215 5450 USA
Department of Neurosurgery University of Debrecen Debrecen 4032 Hungary
Department of Oncology Faculty of Medicine University of Debrecen Debrecen 4032 Hungary
Department of Pathology Montreal Neurological Institute McGill University Montreal QC H3A 2B4 Canada
Department of Pediatrics Harvard Medical School Boston MA 02115 USA
Department of Pediatrics University of Melbourne Parkville VIC 3052 Australia
Developmental and Stem Cell Biology Program The Hospital for Sick Children Toronto ON M5G 0A4 Canada
Division of Orthopedic Surgery Faculty of Surgery McGill University Montreal QC H3G 1A4 Canada
Division of Pediatric Neurooncology German Cancer Consortium Heidelberg 69120 Germany
Hopp Children's Cancer Center Heidelberg Heidelberg 69120 Germany
Kids Cancer Centre Sydney Children's Hospital Randwick NSW 2031 Australia
Lady Davis Research Institute Jewish General Hospital Montreal QC H3T 1E2 Canada
Murdoch Children's Research Institute
Pediatric Glioma Research Group German Cancer Research Center 69120 Heidelberg Germany
Quantitative Life Sciences McGill University Montreal QC H3A 2A7 Canada
School of Computer Science McGill University Montreal QC H3A 2A7 Canada
School of Women's and Children's Health UNSW Sydney Kensington NSW 2052 Australia
References provided by Crossref.org
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