Deep sequencing reveals abundant noncanonical retroviral microRNAs in B-cell leukemia/lymphoma.
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.
Unit of Animal Genomics, Groupe Interdisciplinaire Génoprotéomique Appliquée,  Université de Liège, 4000 Liège,  Belgium.
Nicolas
N
Rosewick
Mélanie
M
Momont
Keith
K
Durkin
Haruko
H
Takeda
Florian
F
Caiment
Yvette
Y
Cleuter
Céline
C
Vernin
Franck
F
Mortreux
Eric
E
Wattel
Arsène
A
Burny
Michel
M
Georges
Anne
A
Van den Broeke
D000818:Animals; D060565:Argonaute Proteins / Q000378:metabolism; D001483:Base Sequence; D002417:Cattle; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D016583:Enzootic Bovine Leukosis / Q000235:genetics* / Q000821:virology*; D015870:Gene Expression; D006609:High Mobility Group Proteins / Q000235:genetics; D015368:Human T-lymphotropic virus 1 / Q000235:genetics; D006801:Humans; D001909:Leukemia Virus, Bovine / Q000235:genetics*; D015448:Leukemia, B-Cell / Q000235:genetics* / Q000662:veterinary / Q000821:virology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000821:virology; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000662:veterinary / Q000821:virology*; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D012320:RNA Polymerase III / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017423:Sequence Analysis, RNA; D012689:Sequence Homology, Nucleic Acid; D012756:Sheep; D012757:Sheep Diseases / Q000235:genetics / Q000821:virology; D020079:Terminal Repeat Sequences
D060565:Argonaute Proteins; D006609:High Mobility Group Proteins; D035683:MicroRNAs; D012334:RNA, Neoplasm; D012367:RNA, Viral; D012320:RNA Polymerase III