Structural insights and functional implications of ENTPD5 splice variants in low-grade adult type diffuse gliomas and glioblastoma.

NTPDase5 is an endoplasmic reticulum nucleotidase that couples anabolism to adaptive bioenergetic responses in tumors with oncogenic alterations. Initially classified as a proto-oncogene due to the induction of a truncated isoform in hamster, it was later suggested that in humans, this isoform results from alternative splicing. This study models the protein structures encoded by ENTPD5 splice variants in gliomas from TCGA, reclassified as oligodendrogliomas and glioblastomas according to the latest WHO criteria, and investigates the functional impact of ENTPD5 transcript variants using Hallmark and KEGG enrichment analyses. We identified two contrasting transcriptomic profiles, defined by the preference for one of two alternative ENTPD5 terminal exons in tumors. Exon 17 usage is linked to a less proliferative but more adaptive state, marked by hormonal and immunomodulatory signatures, whereas exon 19 usage is linked to a highly proliferative state, enriched in signatures of DNA/RNA regulation and reduced microenvironment modulation. These pro-tumor features were not linked to truncated isoforms but to the selective loss of one of five conserved apyrase catalytic domains. Our findings highlight the association between ENTPD5 alternative splicing and glioma transcriptional programs and underscore the need to consider ENTPD5 splice variants in future research and therapy development.