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

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.

• Authors: Nicolas Rosewick, Mélanie Momont, Keith Durkin, Haruko Takeda, Florian Caiment, Yvette Cleuter, Céline Vernin, Franck Mortreux, Eric Wattel, Arsène Burny, Michel Georges, Anne Van den Broeke
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 6 Pg. 2306-11 (Feb 05 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 23345446 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Argonaute Proteins
• High Mobility Group Proteins
• MicroRNAs
• RNA, Neoplasm
• RNA, Viral
• RNA Polymerase III

Topics

• Animals
• Argonaute Proteins (metabolism)
• Base Sequence
• Cattle
• Cell Line, Tumor
• Disease Models, Animal
• Enzootic Bovine Leukosis (genetics, virology)
• Gene Expression
• High Mobility Group Proteins (genetics)
• Human T-lymphotropic virus 1 (genetics)
• Humans
• Leukemia Virus, Bovine (genetics)
• Leukemia, B-Cell (genetics, veterinary, virology)
• Leukemia-Lymphoma, Adult T-Cell (genetics, virology)
• Lymphoma, B-Cell (genetics, veterinary, virology)
• MicroRNAs (chemistry, genetics, metabolism)
• Molecular Sequence Data
• Nucleic Acid Conformation
• RNA Polymerase III (metabolism)
• RNA, Neoplasm (genetics, metabolism)
• RNA, Viral (chemistry, genetics, metabolism)
• Sequence Analysis, RNA
• Sequence Homology, Nucleic Acid
• Sheep
• Sheep Diseases (genetics, virology)
• Terminal Repeat Sequences