Oligodendroglioma is a low-grade primary brain tumour predicted to originate from mutations in the neural stem and/or progenitor cells. We predict significantly co-occurring mutations, metabolic enzyme IDH1, transcriptional repressor CIC, and single-stranded nucleic acid binding protein FUBP1, drive oligodendroglioma by rewiring the transcriptome. Neomorphic mutations in IDH1 occur early in oligodendroglioma evolution, generating genome instability to promote additional lesions, including loss of tumour suppressors CIC and FUBP1. Despite the high frequency, and significant co-occurrence, of IDH1, CIC, and FUBP1 mutations in oligodendroglioma, mechanisms of tumour initiation and progression remain obscure.
We have developed Drosophila oligodendroglioma models via analogous manipulation of Idh (IDH1), Cic (CIC) andPsi (FUBP1) orthologues, alone and in combination, specifically in the neural stem cell lineage of the developing brain. We demonstrate knockdown of either Cic or Psi alone is sufficient to drive proliferation and expansion of the neural lineage, in line with the prediction that CIC and FUBP1 function as tumour suppressors in the brain. Intriguingly, co-knockdown of Cic and Psi increased the proportion of the lineage comprised of neural stem cells; consistent with combined Cic and Psi depletion promoting stemness. Moreover, although the Idh mutant does not alter neural lineage proliferation, Cic or Psi knockdown (alone or in combination) was sufficient to drive expansion in the Idh mutant background. Therefore, this study provides the first rationale for progression of IDH1 mutant oligodendroglioma, whereby subsequent loss-of-function mutations in CIC and FUBP1 functionally interact to enable glioma stem cell over-proliferation and tumour progression despite loss-of-function for this critical metabolic enzyme.