title: Kaposi sarcoma herpesvirus (KSHV) vFLIP oncoprotein induces B cell transdifferentiation and tumorigenesis in mice.
abstract: Kaposi sarcoma herpesvirus (KSHV) is specifically associated with Kaposi sarcoma (KS) and 2 B cell lymphoproliferative diseases, namely primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD). KS, PEL, and MCD are largely incurable and poorly understood diseases most common in HIV-infected individuals. Here, we have revealed the role of viral FLICE-inhibitory protein (vFLIP) in the initiation of PEL and MCD by specifically expressing vFLIP at different stages of B cell differentiation in vivo. Mice showed MCD-like abnormalities and immunological defects including lack of germinal centers (GCs), impaired Ig class switching, and affinity maturation. In addition, they showed increased numbers of cells expressing cytoplasmic IgM-λ, a thus far enigmatic feature of the KSHV-infected cells in MCD. B cell-derived tumors arose at high incidence and displayed Ig gene rearrangement with downregulated expression of B cell-associated antigens, which are features of PEL. Interestingly, these tumors exhibited characteristics of transdifferentiation and acquired expression of histiocytic/dendritic cell markers. These results define immunological functions for vFLIP in vivo and reveal what we believe to be a novel viral-mediated tumorigenic mechanism involving B cell reprogramming. Additionally, the robust recapitulation of KSHV-associated diseases in mice provides a model to test inhibitors of vFLIP as potential anticancer agents.
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065, USA. gib2004@med.cornell.edu
authors.forename: Gianna
authors.initials: G
authors.lastname: Ballon
authors.forename: Kang
authors.initials: K
authors.lastname: Chen
authors.forename: Rocio
authors.initials: R
authors.lastname: Perez
authors.forename: Wayne
authors.initials: W
authors.lastname: Tam
authors.forename: Ethel
authors.initials: E
authors.lastname: Cesarman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001402:B-Lymphocytes / Q000166:cytology*; D002454:Cell Differentiation; D054338:Cell Transdifferentiation; D018572:Disease-Free Survival; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D017578:Immunoglobulin Class Switching; D051379:Mice; D009369:Neoplasms / Q000378:metabolism; D010766:Phosphorylation; D012514:Sarcoma, Kaposi / Q000821:virology*; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014764:Viral Proteins; C481275:viral FLIP protein, Human herpesvirus 8