Chen, CCL;
Deshmukh, S;
Jessa, S;
Hadjadj, D;
Lisi, V;
Andrade, AF;
Faury, D;
... Jabado, N; + view all
(2020)
Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis.
Cell
, 183
(6)
1617-1633.e22.
10.1016/j.cell.2020.11.012.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.cell.2020.11.012 |
| Publisher version: | https://doi.org/10.1016/j.cell.2020.11.012 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript . For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | GSX2, H3.3 G34R/V, PDGFRA, cell-of-origin, chromatin conformation, gliomas, interneuron progenitors, oncohistones, pediatric cancer, single-cell transcriptome |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10116778 |
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