The BCL6 transcriptional program features repression of multiple oncogenes in primary B cells and is deregulated in DLBCL.
The BCL6 transcriptional repressor is required for development of germinal center (GC) B cells and when expressed constitutively causes diffuse large B-cell lymphomas (DLBCLs). We examined genome-wide BCL6 promoter binding in GC B cells versus DLBCLs to better understand its function in these settings. BCL6 bound to both distinct and common sets of functionally related gene in normal GC cells versus DLBCL cells. Certain BCL6 target genes were preferentially repressed in GC B cells, but not DLBCL cells. Several such genes have prominent oncogenic functions, such as BCL2, MYC, BMI1, EIF4E, JUNB, and CCND1. BCL6 and BCL2 expression was negatively correlated in primary DLBCLs except in the presence of BCL2 translocations. The specific BCL6 inhibitor retro-inverso BCL6 peptidomimetic inhibitor-induced expression of BCL2 and other oncogenes, consistent with direct repression effects by BCL6. These data are consistent with a model whereby BCL6 can directly silence oncogenes in GC B cells and counterbalance its own tumorigenic potential. Finally, a BCL6 consensus sequence and binding sites for other physiologically relevant transcription factors were highly enriched among target genes and distributed in a pathway-dependent manner, suggesting that BCL6 forms specific regulatory circuits with other B-cell transcriptional factors.
Ci
Weimin
W
Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
Polo
Jose M
JM
Cerchietti
Leandro
L
Shaknovich
Rita
R
Wang
Ling
L
Yang
Shao Ning
SN
Ye
Kenny
K
Farinha
Pedro
P
Horsman
Douglas E
DE
Gascoyne
Randy D
RD
Elemento
Olivier
O
Melnick
Ari
A
D001402:B-Lymphocytes / Q000378:metabolism*; D001665:Binding Sites; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000378:metabolism / Q000502:physiology*; D051562:Proto-Oncogene Proteins c-bcr / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology
D051560:Proto-Oncogene Proteins c-bcl-6; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr