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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.

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Dataset ID Description Technology Samples
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
Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis.
Cell 183: 2020 1617-1633.e22
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