Specific peptide interference reveals BCL6 transcriptional and oncogenic mechanisms in B-cell lymphoma cells

Nat Med. 2004 Dec;10(12):1329-35. doi: 10.1038/nm1134. Epub 2004 Nov 7.

Abstract

The BTB/POZ transcriptional repressor and candidate oncogene BCL6 is frequently misregulated in B-cell lymphomas. The interface through which the BCL6 BTB domain mediates recruitment of the SMRT, NCoR and BCoR corepressors was recently identified. To determine the contribution of this interface to BCL6 transcriptional and biological properties, we generated a peptide that specifically binds BCL6 and blocks corepressor recruitment in vivo. This inhibitor disrupts BCL6-mediated repression and establishment of silenced chromatin, reactivates natural BCL6 target genes, and abrogates BCL6 biological function in B cells. In BCL6-positive lymphoma cells, peptide blockade caused apoptosis and cell cycle arrest. BTB domain peptide inhibitors may constitute a novel therapeutic agent for B-cell lymphomas.

Publication types

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

MeSH terms

  • Amino Acid Motifs / genetics
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / physiology*
  • Blotting, Western
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic*
  • Genes, Regulator / genetics*
  • Humans
  • Immunoprecipitation
  • Lymphoma, Large B-Cell, Diffuse / genetics
  • Lymphoma, Large B-Cell, Diffuse / metabolism*
  • Mutation / genetics
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Nuclear Receptor Co-Repressor 1
  • Nuclear Receptor Co-Repressor 2
  • Peptides / metabolism*
  • Protein Binding
  • Protein Structure, Tertiary / genetics
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-6
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured

Substances

  • BCL6 protein, human
  • BCOR protein, human
  • DNA-Binding Proteins
  • NCOR1 protein, human
  • NCOR2 protein, human
  • Nuclear Proteins
  • Nuclear Receptor Co-Repressor 1
  • Nuclear Receptor Co-Repressor 2
  • Peptides
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-6
  • Repressor Proteins