Abstract 4050: Bovine leukemia virus small noncoding RNAs are functional elements that regulate replication and contribute to oncogenesis in vivo

Abstract

Abstract Bovine leukemia virus (BLV), a retrovirus closely related to the human T-lymphotropic virus type 1 (HTLV-1), induces lymphocytosis and B-cell leukemia/lymphoma in ruminants. Although the provirus undergoes transcriptional silencing during transformation, BLV-infected tumor cells massively express viral miRNAs from internal Pol III promoters. To understand the mechanisms involved, a provirus isogenic to a wild type molecular clone but devoid of miRNAs was inoculated into calves. High-throughput RNA-sequencing and bioinformatic analyzes indicated that BLV miRNAs modulate expression of genes involved in B-cell receptor signaling, apoptosis, cell activation and immune response (GZMA, FOS, PPT1, ANXA1, MAP2K1 and PIK3CG). Direct and indirect interactions within these regulatory pathways were validated by luciferase reporter assays. In vivo, the deletion of BLV miRNAs reduced proviral loads in the natural host, indicating their biological relevance in viral replication and persistence. Furthermore, oncogenesis was abolished in the ovine experimental model. These observations thus show that BLV miRNAs affect key signaling pathways, promote viral replication and drive oncogenesis. Citation Format: Nicolas Gillet, Malik Hamaidia, Alix de Brogniez, Geronimo Gutierrez, Nathalie Renotte, Michal Reichert, Karina Trono, Luc Willems. Bovine leukemia virus small noncoding RNAs are functional elements that regulate replication and contribute to oncogenesis in vivo. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4050.