title: A microRNA encoded by Kaposi sarcoma-associated herpesvirus promotes B-cell expansion in vivo.
abstract: The human gammaherpesvirus Kaposi sarcoma-associated herpesvirus is strongly linked to neoplasms of endothelial and B-cell origin. The majority of tumor cells in these malignancies are latently infected, and latency genes are consequently thought to play a critical role in virus-induced tumorigenesis. One such factor is kshv-miR-K12-11, a viral microRNA that is constitutively expressed in cell lines derived from KSHV-associated tumors, and that shares perfect homology of its seed sequence with the cellular miR-155. Since miR-155 is overexpressed in a number of human tumors, it is conceivable that mimicry of miR-155 by miR-K12-11 may contribute to cellular transformation in KSHV-associated disease. Here, we have performed a side-by-side study of phenotypic alterations associated with constitutive expression of either human miR-155 or viral miR-K12-11 in bone marrow-derived hematopoietic stem cells. We demonstrate that retroviral-mediated gene transfer and hematopoietic progenitor cell transplantation into C57BL/6 mice leads to increased B-cell fractions in lymphoid organs, as well as to enhanced germinal center formation in both microRNA-expressing mouse cohorts. We furthermore identify Jarid2, a component of Polycomb repressive complex 2, as a novel validated target of miR-K12-11, and confirm its downregulation in miR-K12-11 as well as miR-155 expressing bone marrow cells. Our findings confirm and extend previous observations made in other mouse models, and underscore the notion that miR-K12-11 may have arisen to mimic miR-155 functions in KSHV-infected B-cells. The expression of miR-K12-11 may represent one mechanism by which KSHV presumably aims to reprogram naïve B-cells towards supporting long-term latency, which at the same time is likely to pre-dispose infected lymphocytes to malignant transformation.
authors.affiliation: Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Dahlke
authors.forename: Katrin
authors.initials: K
authors.lastname: Maul
authors.forename: Thomas
authors.initials: T
authors.lastname: Christalla
authors.forename: Nicole
authors.initials: N
authors.lastname: Walz
authors.forename: Philipp
authors.initials: P
authors.lastname: Schult
authors.forename: Carol
authors.initials: C
authors.lastname: Stocking
authors.forename: Adam
authors.initials: A
authors.lastname: Grundhoff
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000821:virology*; D001854:Bone Marrow Cells / Q000166:cytology; D049109:Cell Proliferation; D018014:Gene Transfer Techniques; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000821:virology; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000378:metabolism*
chemical_list: C524942:MIRN155 microRNA, human; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D012367:RNA, Viral