Histone-mutant interneuron progenitors co-opt PDGFRA for gliomagenesis

Histone H3.3 glycine 34 arginine/valine (G34R/V) mutations occur in deadly hemispheric high-grade gliomas. These mutations show exquisite regional and temporal specificity, which suggests a developmental context permissive to their effects. Here we present the molecular landscape of G34R/V tumours (n=86) and show that 50% bear activating mutations in PDGFRA , with strong selection pressure for PDGFRA -mutant clones at recurrence. We show that, while they are considered gliomas, G34R/V tumours arise in foetal interneuron progenitors derived from the ventral forebrain, which express GSX2 and DLX homeobox transcription factors. Further neuronal differentiation is impaired in these progenitors by G34R/V. High expression and frequent mutations of PDGFRA in G34R/V HGGs are facilitated in this lineage-of-origin, where PDGFRA forms a chromatin loop with the adjacent GSX2 , hijacking its active chromatin conformation. At the single-cell level, G34R/V tumours harbour dual neuronal/astroglial cell identities and lack oligodendroglial programs, that are actively repressed by GSX2/DLX -mediated cell-fate specification. G34R/V CRISPR-removal does not impact tumorigenicity suggesting this mutation becomes dispensable, while PDGFRA mutations are potent oncogenic drivers. Collectively, our results suggest that G34R/V gliomas arise in foetal inhibitory interneuron progenitors where they stall differentiation and co-opt PDGFRA via inappropriate expression and activating mutations to promote oncogenicity and gliogenesis. assessed and interpreted histopathology results. A.B. and A.S.H. performed experiments and data analysis/interpretation. D.M.M. and B.G. led the histone proteomics experiments and analysis. L.G.M. facilitated patient sample acquisition and contributed to manuscript preparation. N. Juretic facilitated patient sample acquisition. A.V.B. and A.M.B. performed in silico modelling of PDGFRA mutations. P.H., A.K., M.Z., A.V., L.K., K.V., J.Z., D.S., P.G.E, D.S.Z., J.R.H., D.A.K.Q., and A.G.W collected patient samples. L.G., R.B., M.D.T., P.B, D.T.W.J, and P.S. contributed to study design and data interpretation. C.L.K. and N.J. co-led and supervised all aspects of the project.

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