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

Nicolas Rosewick, Melanie Momont, Keith Durkin, Haruko Takeda, Florian Caiment, Yvette Cleuter, Celine Vernin, Franck Mortreux, Eric Wattel, Arsene Burny, Michel Georges, Anne Van den Broeke*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

70 Citations (Web of Science)

Abstract

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.
Original languageEnglish
Pages (from-to)2306-2311
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number6
DOIs
Publication statusPublished - 5 Feb 2013

Keywords

  • noncoding RNA
  • oncogenesis
  • retrovirus silencing
  • HTLV-1

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