H3.3G34R/V-transformed interneuron progenitors co-opt PDGFRA for gliomagenesis
Histone H3.3 glycine 34 to arginine/valine (H3.3G34R/V) mutations occur in deadly hemispheric high-grade gliomas. These tumors show exquisite regional and temporal specificity, suggesting a developmental context permissive to the effects of G34R/V mutations. Here we present the molecular landscape of G34R/V gliomas (n=85) and show that 50% bear activating mutations in PDGFRA, with strong selection pressure for PDGFRAMUT clones at recurrence. We show that G34R/V tumors arise in interneuron progenitors of the foetal ventral forebrain expressing GSX2 and the DLX family of homeobox transcription factors, where terminal neuronal differentiation is impaired through aberrant G34R/V-mediated H3K27me3. Frequent co-occurrence of G34R/V & PDGFRAMUT is facilitated in this interneuron lineage-of-origin as PDGFRA forms an aberrant chromatin loop with the adjacent GSX2, hijacking its active chromatin conformation. At the single-cell level, G34R/V tumours entirely lack oligodendroglial transcriptional programs prominent in other glioma entities, and instead harbour dual neuronal and astroglial compartments. CRISPR-removal of H3.3G34R/V does not impact tumorigenicity suggesting this mutation becomes dispensable, while PDGFRAMUT are potently oncogenic regardless of G34 mutation. Collectively, our results suggest that G34R/V gliomas arise in foetal interneuron progenitors unable to undergo terminal differentiation, enabling co-option of PDGFRA through inappropriate expression and activating mutations to promote gliogenesis and oncogenicity. Reliance on PDGFRA for oncogenesis may be of therapeutic opportunity in G34R/V glioma.
- Type: Other
- Archiver: European Genome-Phenome Archive (EGA)
Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data
Dataset ID | Description | Technology | Samples |
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EGAD00001006097 | Illumina HiSeq 4000 Illumina NovaSeq 6000 | 21 | |
EGAD00001006098 | Illumina HiSeq 2000 Illumina HiSeq 4000 Illumina NovaSeq 6000 unspecified | 20 | |
EGAD00001006099 | Illumina HiSeq 2000 Illumina HiSeq 2500 Illumina HiSeq 4000 unspecified | 27 | |
EGAD00001006100 | Illumina HiSeq 2000 Illumina HiSeq 2500 Illumina NovaSeq 6000 | 78 |
Publications | Citations |
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Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis.
Cell 183: 2020 1617-1633.e22 |
85 |
Dissecting the tumor microenvironment of epigenetically driven gliomas: Opportunities for single-cell and spatial multiomics.
Neurooncol Adv 5: 2023 vdad101 |
0 |
Immune landscape of oncohistone-mutant gliomas reveals diverse myeloid populations and tumor-promoting function.
Nat Commun 15: 2024 7769 |
0 |