Deep sequencing reveals abundant noncanonical retroviral microRNAs in B-cell leukemia/lymphoma

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 6; pp. 2306 - 2311
• Main Authors: Rosewick, Nicolas, Momont, Mélanie, Durkin, Keith, Takeda, Haruko, Caiment, Florian, Cleuter, Yvette, Vernin, Céline, Mortreux, Franck, Wattel, Eric, Burny, Arsène, Georges, Michel, Van den Broeke, Anne
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05.02.2013; National Acad Sciences
• Subjects: animal models; Animals; Argonaute Proteins - metabolism; B lymphocytes; Base Sequence; Biological Sciences; Bovine leukemia virus; Cattle; Cell Line, Tumor; Cells; Disease Models, Animal; DNA-directed RNA polymerase; Enzootic Bovine Leukosis - genetics; Enzootic Bovine Leukosis - virology; Gene Expression; High Mobility Group Proteins - genetics; High throughput nucleotide sequencing; Human T-lymphotropic virus 1 - genetics; Humans; Leukemia; Leukemia Virus, Bovine - genetics; Leukemia, B-Cell - genetics; Leukemia, B-Cell - veterinary; Leukemia, B-Cell - virology; Leukemia-Lymphoma, Adult T-Cell - genetics; Leukemia-Lymphoma, Adult T-Cell - virology; Lymphoma; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - veterinary; Lymphoma, B-Cell - virology; Messenger RNA; MicroRNA; MicroRNAs - chemistry; MicroRNAs - genetics; MicroRNAs - metabolism; Molecular Sequence Data; Nucleic Acid Conformation; pathogenicity; Proviruses; regulator genes; Ribonucleic acid; RNA; RNA polymerase; RNA Polymerase III - metabolism; RNA, Neoplasm - genetics; RNA, Neoplasm - metabolism; RNA, Viral - chemistry; RNA, Viral - genetics; RNA, Viral - metabolism; Sequence Analysis, RNA; Sequence Homology, Nucleic Acid; Sheep; Sheep Diseases - genetics; Sheep Diseases - virology; Terminal Repeat Sequences; transcription (genetics); Tumors; Viruses
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1213842110

Viral tumor models have significantly contributed to our understanding of oncogenic mechanisms. How transforming delta-retroviruses induce malignancy, however, remains poorly understood, especially as viral mRNA/protein are tightly silenced in tumors. Here, using deep sequencing of broad windows of small RNA sizes in the bovine leukemia virus ovine model of leukemia/lymphoma, we provide in vivo evidence of the production of noncanonical RNA polymerase III (Pol III)-transcribed viral microRNAs in leukemic B cells in the complete absence of Pol II 5′-LTR–driven transcriptional activity. Processed from a cluster of five independent self-sufficient transcriptional units located in a proviral region dispensable for in vivo infectivity, bovine leukemia virus microRNAs represent ∼40% of all microRNAs in both experimental and natural malignancy. They are subject to strong purifying selection and associate with Argonautes, consistent with a critical function in silencing of important cellular and/or viral targets. Bovine leukemia virus microRNAs are strongly expressed in preleukemic and malignant cells in which structural and regulatory gene expression is repressed, suggesting a key role in tumor onset and progression. Understanding how Pol III-dependent microRNAs subvert cellular and viral pathways will contribute to deciphering the intricate perturbations that underlie malignant transformation.