A virus-encoded telomerase RNA promotes malignant T cell lymphomagenesis

J Exp Med. 2006 May 15;203(5):1307-17. doi: 10.1084/jem.20052240. Epub 2006 May 1.

Abstract

Telomerase is a ribonucleoprotein complex consisting of two essential core components: a reverse transcriptase and an RNA subunit (telomerase RNA [TR]). Dysregulation of telomerase has been associated with cell immortalization and oncogenesis. Marek's disease herpesvirus (MDV) induces a malignant T cell lymphoma in chickens and harbors in its genome two identical copies of a viral TR (vTR) with 88% sequence identity to chicken TR. MDV mutants lacking both copies of vTR were significantly impaired in their ability to induce T cell lymphomas, although lytic replication in vivo was unaffected. Tumor incidences were reduced by >60% in chickens infected with vTR- viruses compared with animals inoculated with MDV harboring at least one intact copy of vTR. Lymphomas in animals infected with the vTR- viruses were also significantly smaller in size and less disseminated. Constitutive expression of vTR in the chicken fibroblast cell line DF-1 resulted in a phenotype consistent with transformation as indicated by morphological alteration, enhanced anchorage-independent cell growth, cell growth beyond saturation density, and increased expression levels of integrin alpha v. We concluded that vTR plays a critical role in MDV-induced T cell lymphomagenesis. Furthermore, our results provide the first description of tumor-promoting effects of TR in a natural virus-host infection model.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Cell Transformation, Viral*
  • Chickens
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Fibroblasts / virology
  • Gene Expression Regulation, Leukemic / physiology
  • Gene Expression Regulation, Viral / physiology
  • Genome
  • Integrin alpha Chains / biosynthesis
  • Integrin beta Chains / biosynthesis
  • Lymphoma, T-Cell / enzymology*
  • Lymphoma, T-Cell / genetics
  • Lymphoma, T-Cell / pathology
  • Lymphoma, T-Cell / virology
  • Mardivirus / enzymology*
  • Mardivirus / genetics
  • Marek Disease / enzymology
  • Marek Disease / genetics
  • Marek Disease / pathology
  • Marek Disease / virology
  • Mutation
  • Sequence Homology, Amino Acid
  • Telomerase / genetics
  • Telomerase / metabolism*
  • Viral Proteins / genetics
  • Viral Proteins / metabolism*

Substances

  • Integrin alpha Chains
  • Integrin beta Chains
  • Viral Proteins
  • Telomerase