Kaposi Sarcoma Herpesvirus (KSHV) vFLIP Oncoprotein Induces B Cell Transdifferentiation and Tumorigenesis in Mice

J Clin Invest. 2011 Mar;121(3):1141-53. doi: 10.1172/JCI44417. Epub 2011 Feb 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • B-Lymphocytes / cytology*
  • Cell Differentiation
  • Cell Transdifferentiation
  • Disease-Free Survival
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic*
  • Herpesvirus 8, Human / metabolism*
  • Humans
  • Immunoglobulin Class Switching
  • Mice
  • Neoplasms / metabolism
  • Phosphorylation
  • Sarcoma, Kaposi / virology*
  • Viral Proteins / genetics*
  • Viral Proteins / metabolism

Substances

  • Antineoplastic Agents
  • Viral Proteins
  • viral FLIP protein, Human herpesvirus 8