BCL6 suppression of BCL2 via Miz1 and its disruption in diffuse large B cell lymphoma

Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11294-9. doi: 10.1073/pnas.0903854106. Epub 2009 Jun 23.

Abstract

The BCL6 proto-oncogene encodes a transcriptional repressor that is required for germinal center (GC) formation and whose deregulation by genomic lesions is implicated in the pathogenesis of GC-derived diffuse large B cell lymphoma (DLBCL) and, less frequently, follicular lymphoma (FL). The biological function of BCL6 is only partially understood because no more than a few genes have been functionally characterized as direct targets of BCL6 transrepression activity. Here we report that the anti-apoptotic proto-oncogene BCL2 is a direct target of BCL6 in GC B cells. BCL6 binds to the BCL2 promoter region by interacting with the transcriptional activator Miz1 and suppresses Miz1-induced activation of BCL2 expression. BCL6-mediated suppression of BCL2 is lost in FL and DLBCL, where the 2 proteins are pathologically coexpressed, because of BCL2 chromosomal translocations and other mechanisms, including Miz1 deregulation and somatic mutations in the BCL2 promoter region. These results identify an important function for BCL6 in facilitating apoptosis of GC B cells via suppression of BCL2, and suggest that blocking this pathway is critical for lymphomagenesis.

Publication types

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

MeSH terms

  • B-Lymphocytes / metabolism
  • Cell Line, Tumor
  • DNA Mutational Analysis
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Germinal Center / cytology
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / metabolism*
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Mutation / genetics
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Protein Inhibitors of Activated STAT / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Proto-Oncogene Proteins c-bcl-6
  • Somatic Hypermutation, Immunoglobulin / genetics
  • Transcription, Genetic
  • Translocation, Genetic

Substances

  • BCL6 protein, human
  • DNA-Binding Proteins
  • PIAS2 protein, human
  • Protein Inhibitors of Activated STAT
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins c-bcl-6