A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma.
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.
Saito
Masumichi
M
Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
Gao
Jie
J
Basso
Katia
K
Kitagawa
Yukiko
Y
Smith
Paula M
PM
Bhagat
Govind
G
Pernis
Alessandra
A
Pasqualucci
Laura
L
Dalla-Favera
Riccardo
R
D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D015536:Down-Regulation; D018858:Germinal Center / Q000276:immunology*; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000235:genetics*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D051560:Proto-Oncogene Proteins c-bcl-6; D015398:Signal Transduction; D014158:Transcription, Genetic; D014178:Translocation, Genetic; D000099218:Interferon Regulatory Factor-4