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Kaposi sarcoma herpesvirus (KSHV) vFLIP oncoprotein induces B cell transdifferentiation and tumorigenesis in mice
Gianna Ballon, … , Wayne Tam, Ethel Cesarman
Gianna Ballon, … , Wayne Tam, Ethel Cesarman
Published February 21, 2011
Citation Information: J Clin Invest. 2011;121(3):1141-1153. https://doi.org/10.1172/JCI44417.
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Research Article

Kaposi sarcoma herpesvirus (KSHV) vFLIP oncoprotein induces B cell transdifferentiation and tumorigenesis in mice

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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

Gianna Ballon, Kang Chen, Rocio Perez, Wayne Tam, Ethel Cesarman

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Figure 1

Generation of ROSA26.vFLIP;CD19.cre and ROSA26.vFLIP;Cγ1.cre mice.

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Generation of ROSA26.vFLIP;CD19.cre and ROSA26.vFLIP;Cγ1.cre mice.
(A) S...
(A) Schematic representation of the ROSA26 locus before (top) and after (bottom) homologous recombination with the targeting vector (middle) carrying a triple-flagged vFLIP encoding sequence. (B) A representative Southern blot analysis of EcoRI- or BglI-digested WT and recombinant (R) ES cell DNA. Probes used and expected genomic fragment sizes are also indicated. (C) The strategy for recombinant activation of vFLIP expression in vivo. ROSA26.vFLIP knockin mice were bred with either CD19.cre or Cγ1.cre mice to obtain Tg expression from early precursor B cell stage or from GC stage, respectively. (D) Tg expression was specifically detected, both by RT-PCR (upper panel) and anti-FLAG immunoblotting (lower panel) in splenic CD19+ B cells derived from both ROSA26.vFLIP;CD19.cre and ROSA26.vFLIP;Cγ1.cre mice. Sample lanes separated by thin white lines were run on the same gel but were noncontiguous. Tg*, ROSA26.vFLIP;CD19.cre mice used for positive control; Spl, spleen; Thy, thymus.
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