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 March 1, 2011; First 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

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 8

Model of vFLIP-mediated tumorigenesis, cell reprogramming, and paracrine stimulation of histiocytic/DCs.

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Model of vFLIP-mediated tumorigenesis, cell reprogramming, and paracrine...
The expression of KSHV vFLIP alone in B cells initially results in pathological alterations mimicking MCD and eventually leads to the development of B cell–derived tumors via transdifferentiation, as evidenced by the biphenotypic features of the tumor cells (i.e., phenotypically macrophage/DCs, genotypically B cells). This surprising phenotype has a correspondence in human pathology (i.e., development of follicular/DC sarcoma in a patient with previously diagnosed Castleman disease) and underlines an existing plasticity between B cell and macrophage/DC lineages, as recently reported also for other B cell malignancies (e.g., FL). Moreover, the expansion of phenotypically and genotypically genuine macrophage/DCs, as observed in the Tg mouse spleen, suggests that vFLIP-expressing B cells can sustain the proliferation of this compartment also via a paracrine mechanism. This process may contribute to the cell heterogeneity seen in KS, which is typically characterized by abundant histiocytic infiltrate of unknown origin and function.