Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article

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

  • Text
  • PDF
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

×

Figure 8

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

Options: View larger image (or click on image) Download as PowerPoint
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.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts