Functional interplay of Epstein-Barr virus oncoproteins in a mouse model of B cell lymphomagenesis

Autor/innen

  • T. Sommermann
  • T. Yasuda
  • J. Ronen
  • T. Wirtz
  • T. Weber
  • U. Sack
  • R. Caeser
  • J. Zhang
  • X. Li
  • V.T. Chu
  • A. Jauch
  • K. Unger
  • D.J. Hodson
  • A. Akalin
  • K. Rajewsky

Journal

  • Proceedings of the National Academy of Sciences of the United States of America

Quellenangabe

  • Proc Natl Acad Sci U S A 117 (25): 14421-14432

Zusammenfassung

  • Epstein-Barr virus (EBV) is a B cell transforming virus that causes B cell malignancies under conditions of immune suppression. EBV orchestrates B cell transformation through its latent membrane proteins (LMPs) and Epstein-Barr nuclear antigens (EBNAs). We here identify secondary mutations in mouse B cell lymphomas induced by LMP1, to predict and identify key functions of other EBV genes during transformation. We find aberrant activation of early B cell factor 1 (EBF1) to promote transformation of LMP1-expressing B cells by inhibiting their differentiation to plasma cells. EBV EBNA3A phenocopies EBF1 activities in LMP1-expressing B cells, promoting transformation while inhibiting differentiation. In cells expressing LMP1 together with LMP2A, EBNA3A only promotes lymphomagenesis when the EBNA2 target Myc is also overexpressed. Collectively, our data support a model where proproliferative activities of LMP1, LMP2A, and EBNA2 in combination with EBNA3A-mediated inhibition of terminal plasma cell differentiation critically control EBV-mediated B cell lymphomagenesis.


DOI

doi:10.1073/pnas.1921139117