INTRODUCTION: Isocitrate dehydrogenase (IDH) mutations define a molecular subset of diffuse gliomas that exhibit slower growth yet ultimately progress and resist treatment. These mutations confer a neomorphic enzymatic activity that leads to accumulation of the oncometabolite D-2-hydroxyglutarate (D-2HG), which reshapes the epigenetic landscape by inhibiting α-ketoglutarate–dependent dioxygenases. While the effects of D-2HG on DNA and histone methylation are well documented, its influence on RNA demethylases regulating N6-methyladenosine (m6A) remains largely unexplored. 

AIM(S): Investigating how intracellular D-2HG alters the m6A epitranscriptome of glioma cells and facilitates tumor-neuron communication in IDH-mutant gliomas.

METHOD(S): Using IDH-mutant glioma cells treated or not with an IDH inhibitor to deplete D-2HG, we perform direct RNA nanopore sequencing to map transcriptome-wide m6A changes.

RESULTS: Our preliminary data suggest that D-2HG inhibits FTO activity and promotes m6A accumulation, particularly on transcripts related to synaptic signaling, leading to their stabilization. The functional consequences of these modifications will be assessed through co-culture of neurons with IDH-mutant glioma cells, combined with electrophysiology and calcium imaging. We aim to demonstrate that glioma m6A remodeling enhances glutamatergic signaling toward tumor cells, thereby promoting their proliferation and invasion. Silencing of candidate m6A-modified transcripts will be used to validate their contribution to these effects. 

CONCLUSIONS: By unveiling a novel mechanism through which a tumor-derived metabolite alters RNA regulation to support glioma progression, this study highlights m6A as a key player in neurogliomal crosstalk and a potential therapeutic axis in IDH-mutant gliomas. 

FINANCIAL SUPPORT: La Ligue contre le cancer