A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma

Cancer Cell. 2007 Sep;12(3):280-92. doi: 10.1016/j.ccr.2007.08.011.

Abstract

The BCL6 proto-oncogene encodes a transcriptional repressor necessary for the development of germinal centers (GCs) and directly implicated in lymphomagenesis. Post-GC development of B cells requires BCL6 downregulation, while its constitutive expression caused by chromosomal translocations leads to diffuse large B cell lymphoma (DLBCL). Herein we identify a signaling pathway that downregulates BCL6 expression in normal GC B cells and is blocked in a subset of DLBCL due to alterations in the BCL6 gene. Activation of the CD40 receptor leads to NF-kappaB-mediated induction of the IRF4 transcription factor, which, in turn, represses BCL6 expression by binding to its promoter region. A subset of DLBCL displays chromosomal translocations or mutations that disrupt the IRF4-responsive region in the BCL6 promoter and block its downregulation by CD40 signaling.

Publication types

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

MeSH terms

  • B-Lymphocytes / immunology*
  • CD40 Antigens / metabolism
  • DNA-Binding Proteins / genetics*
  • Down-Regulation*
  • Germinal Center / immunology*
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism
  • Lymphoma, B-Cell / genetics*
  • Lymphoma, Large B-Cell, Diffuse / genetics*
  • Mutation
  • NF-kappa B / metabolism
  • Proto-Oncogene Proteins c-bcl-6
  • Signal Transduction*
  • Transcription, Genetic
  • Translocation, Genetic

Substances

  • BCL6 protein, human
  • CD40 Antigens
  • DNA-Binding Proteins
  • Interferon Regulatory Factors
  • NF-kappa B
  • Proto-Oncogene Proteins c-bcl-6
  • interferon regulatory factor-4