Requirement for LMP1-induced RON receptor tyrosine kinase in Epstein-Barr virus-mediated B-cell proliferation

Blood. 2011 Aug 4;118(5):1340-9. doi: 10.1182/blood-2011-02-335448. Epub 2011 Jun 9.

Abstract

EBV, an oncogenic human herpesvirus, can transform primary B lymphocytes into immortalized lymphoblastoid cell lines (LCLs) through multiple regulatory mechanisms. However, the involvement of protein tyrosine kinases in the infinite proliferation of B cells is not clear. In this study, we performed kinase display assays to investigate this subject and identified a specific cellular target, Recepteur d'Origine Nantais (RON) tyrosine kinase, expressed in LCLs but not in primary B cells. Furthermore, we found that latent membrane protein 1 (LMP1), an important EBV oncogenic protein, enhanced RON expression through its C-terminal activation region-1 (CTAR1) by promoting NF-κB binding to the RON promoter. RON knockdown decreased the proliferation of LCLs, and transfection with RON compensated for the growth inhibition caused by knockdown of LMP1. Immunohistochemical analysis revealed a correlation between LMP1 and RON expression in biopsies from posttransplantation lymphoproliferative disorder (PTLD), suggesting that LMP1-induced RON expression not only is essential for the growth of LCLs but also may contribute to the pathogenesis of EBV-associated PTLD. Our study is the first to reveal the impact of RON on the proliferation of transformed B cells and to suggest that RON may be a novel therapeutic target for EBV-associated lymphoproliferative diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / physiology*
  • Cell Line, Tumor
  • Cell Proliferation* / drug effects
  • Enzyme Induction
  • Epstein-Barr Virus Infections / complications
  • Epstein-Barr Virus Infections / genetics
  • Epstein-Barr Virus Infections / immunology
  • Epstein-Barr Virus Infections / pathology
  • Gene Expression Regulation, Enzymologic
  • Gene Knockdown Techniques
  • Herpesvirus 4, Human / immunology
  • Herpesvirus 4, Human / physiology*
  • Humans
  • Lymphoproliferative Disorders / etiology
  • Lymphoproliferative Disorders / genetics
  • Lymphoproliferative Disorders / immunology
  • Receptor Protein-Tyrosine Kinases / biosynthesis*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Signal Transduction / genetics
  • Viral Matrix Proteins / metabolism
  • Viral Matrix Proteins / pharmacology
  • Viral Matrix Proteins / physiology*

Substances

  • EBV-associated membrane antigen, Epstein-Barr virus
  • Viral Matrix Proteins
  • RON protein
  • Receptor Protein-Tyrosine Kinases