Abstract 3170: Human retroviral sequences transcription in glioma/glioblastoma sample

Abstract In glioblastoma patients, expansion of glioma initiating cells (GICs), a discrete population of cells demonstrating stem-like phenotype, is often associated with drug resistance development and ultimately cancer recurrence. Therefore a better understanding of the molecular and cellular mechanisms underlying the origin of GICs is critical to develop new therapies better targeting glioblastoma. Human endogenous retroviral sequences (HERVs), present in approximately 500,000 copies and comprising nearly 8% of the human genome, may serve as an abundant genetic material equipping GIC with phenotypic plasticity needed to develop stem-like phenotype. Recent epigenomic and transcriptomic data show HERV activation during early human development. Moreover, increased HERV transcription is observed in OCT4/SOX2/KLF4/c-MYC induced pluripotent cells. Finally, activation of HERV loci transcription is also commonly observed in different tumor types. Using publicly available The Cancer Genome Atlas Glioblastoma Multiforme (TCGA-GBM) RNA-seq data collection, we have quantified transcripts for all 13,208 HERV loci annotated in the RepBase database. To improve the accuracy of quantifying the HERV transcriptomic landscape, we reassigned already mapped fragments to the most probable transcript using the Telescope software. Our comprehensive approach allowed us to identify the set of HERV loci uniquely dysregulated in the glioblastoma compared to normal brain tissue. In addition, we compared 540 low-grade glial tumors from TCGA-LGG project (classified as grade II and III gliomas) with 165 glioblastoma samples from TCGA-GBM (classified as grade IV gliomas) using the same bioinformatics pipeline. Comprehensive analysis of transcript levels allowed us to identify HERV assemblage differentially expressed between these two patient cohorts. The correlation between HERV and ORF transcript levels show strong coregulation of HERVs expression with genes involved in establishing/maintaining embryonic/neural/glial stem cells phenotype. To confirm our observations we have up- or downregulated HERV loci combining guide RNA array targeting robustly approximately 90% of HERV LTR5Hs elements with a vector expressing CRISPR-based transcriptional activator or repressor. Downregulation of HERV transcription with this system was associated with the inhibition of clonogenic growth in cell culture. In summary, this study sets the stage for identifying HERV loci that could serve as potential GIC biomarkers, as well as the molecular targets for GIC elimination. Citation Format: Adam J. Lassak, Monika Rak, Melody C. Baddoo, Hui-Yi Lin, Krzysztof Reiss. Human retroviral sequences transcription in glioma/glioblastoma sample [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3170.