IBCL-306: Simultaneous Analysis of Oncolytic Viruses Reproduction and RNAseq Transcriptome Data in Short-Term Lymphoid Cultures for Identification of Biomarkers for Viral Therapy Effectiveness Prediction

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Introduction: B-cell lymphoproliferative diseases are a heterogeneous group of tumors that differ in morphology, clinical presentation, and cytogenetic characteristics. Despite the significant contribution of therapy, the problem of tumor cells resistant to chemotherapy and relapses remains. One of the promising approaches is the use of oncolytic enteroviruses that could lyse tumor cells of lymphoid origin. Objective: The goal of the study was to determine the genes and signaling pathways, associated with the effectiveness of viral oncolysis in short-term lymphoid cultures. Materials and Methods: The replication efficiency of six oncolytic strains (LEV14-Coxsackievirus B5, LEV7-Echovirus 12, PV1S-vaccine strain of type 1 poliovirus (Sabin), LEV8-Coxsackievirus A7, LEV15-Coxsackievirus B6, and vesicular stomatitis virus strain Indiana) was estimated in 16 short-term cultures of non-Hodgkin lymphomas. Transcriptome sequencing for evaluation of differentially expressed (DE) genes was performed on the Illumina HiSeq platform. Results: Short-term lymphoid cultures most effectively replicated strains LEV14, ECHO12, and PV1S. There were no correlations with the clinical characteristics of lymphomas. The analysis of DE genes in culture cells capable and not capable of efficient replication of non-pathogenic strains followed by enrichment analysis revealed key signaling pathways involved in the process of viral oncolysis (in particular, the signaling pathway of endocytosis). It is worth noting the important role of phospholipase D2 (PLD2); the high level of its expression is associated with the ability of enteroviruses to replicate in tumor cells (p = 0.007). PLD2 is involved in both clathrin-dependent and clathrin-independent endocytosis. Knockout of this gene in model cell lines led to inability of enteroviruses to replicate efficiently in these cells. Conclusion: The identification of DE genes and involved signaling pathways is an effective tool for studying the biology of viral oncolysis in tumor cells of lymphoid origin.