title: A Kaposi's sarcoma-associated herpesvirus-encoded ortholog of microRNA miR-155 induces human splenic B-cell expansion in NOD/LtSz-scid IL2Rγnull mice.
abstract: MicroRNAs (miRNAs) are small noncoding RNA molecules that function as posttranscriptional regulators of gene expression. Kaposi's sarcoma (KS)-associated herpesvirus (KSHV), a B-cell-tropic virus associated with KS and B-cell lymphomas, encodes 12 miRNA genes that are highly expressed in these tumor cells. One viral miRNA, miR-K12-11, shares 100% seed sequence homology with hsa-miR-155, an oncogenic human miRNA that functions as a key regulator of hematopoiesis and B-cell differentiation. So far, in vitro studies have shown that both miRNAs can regulate a common set of cellular target genes, suggesting that miR-K12-11 may mimic miR-155 function. To comparatively study miR-K12-11 and miR-155 function in vivo, we used a foamy virus vector to express the miRNAs in human hematopoietic progenitors and performed immune reconstitutions in NOD/LtSz-scid IL2Rγ(null) mice. We found that ectopic expression of miR-K12-11 or miR-155 leads to a significant expansion of the CD19(+) B-cell population in the spleen. Subsequent quantitative PCR analyses of these splenic B cells revealed that C/EBPβ, a transcriptional regulator of interleukin-6 that is linked to B-cell lymphoproliferative disorders, is downregulated when either miR-K12-11 or miR-155 is ectopically expressed. In addition, inhibition of miR-K12-11 function using antagomirs in KSHV-infected human primary effusion lymphoma B cells resulted in derepression of C/EBPβ transcript levels. This in vivo study validates miR-K12-11 as a functional ortholog of miR-155 in the context of hematopoiesis and suggests a novel mechanism by which KSHV miR-K12-11 induces splenic B-cell expansion and potentially KSHV-associated lymphomagenesis by targeting C/EBPβ.
authors.affiliation: Department of Molecular Genetics and Microbiology, University of Florida,Gainesville, FL, USA.
authors.forename: Isaac W
authors.initials: IW
authors.lastname: Boss
authors.forename: Peter E
authors.initials: PE
authors.lastname: Nadeau
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Abbott
authors.forename: Yajie
authors.initials: Y
authors.lastname: Yang
authors.forename: Ayalew
authors.initials: A
authors.lastname: Mergia
authors.forename: Rolf
authors.initials: R
authors.lastname: Renne
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000032:analysis; D001402:B-Lymphocytes / Q000502:physiology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000096:biosynthesis; D049109:Cell Proliferation; D015536:Down-Regulation; D019288:Herpesvirus 8, Human / Q000472:pathogenicity*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D012367:RNA, Viral / Q000235:genetics* / Q000378:metabolism*; D013154:Spleen / Q000166:cytology
chemical_list: D018941:Antigens, CD19; D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D012367:RNA, Viral