BCL6 suppression of BCL2 via Miz1 and its disruption in diffuse large B cell lymphoma.
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.
Saito
Masumichi
M
Institute for Cancer Genetics, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
Novak
Urban
U
Piovan
Erich
E
Basso
Katia
K
Sumazin
Pavel
P
Schneider
Christof
C
Crespo
Marta
M
Shen
Qiong
Q
Bhagat
Govind
G
Califano
Andrea
A
Chadburn
Amy
A
Pasqualucci
Laura
L
Dalla-Favera
Riccardo
R
D001402:B-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D018858:Germinal Center / Q000166:cytology; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051560:Proto-Oncogene Proteins c-bcl-6; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics; D014158:Transcription, Genetic; D014178:Translocation, Genetic
C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; C501001:PIAS2 protein, human; D050828:Protein Inhibitors of Activated STAT; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2; D051560:Proto-Oncogene Proteins c-bcl-6