Control of Inflammation, Cytokine Expression, and Germinal Center Formation by BCL-6

Abstract

The gene encoding the BCL-6 transcriptional repressor is frequently translocated and mutated in diffuse large cell lymphoma. Mice with a disrupted BCL-6 gene developed myocarditis and pulmonary vasculitis, had no germinal centers, and had increased expression of T helper cell type 2 cytokines. The BCL-6 DNA recognition motif resembled sites bound by the STAT (signal transducers and activators of transcription) transcription factors, which mediate cytokine signaling. BCL-6 could repress interleukin-4 (IL-4)-induced transcription when bound to a site recognized by the IL-4-responsive transcription factor Stat6. Thus, dysregulation of STAT-responsive genes may underlie the inflammatory disease in BCL-6-deficient mice and participate in lymphoid malignancies.

The biology of Stat4 and Stat6

“…Although Bcl-6 does not resemble Stat6 structurally, Bcl-6 is capable of recognizing the Stat6-speci®c DNA binding site (Dent et al, 1997). When Bcl-6 is overexpressed it can block the ability of Stat6 to transactivate the CD23 promoter by presumably competing for the Stat6 binding site (Dent et al, 1997). These in vitro observations are supported by the in vivo observations made in Bcl-6-de®cient mice (Dent et al, 1997).…”

“…When Bcl-6 is overexpressed it can block the ability of Stat6 to transactivate the CD23 promoter by presumably competing for the Stat6 binding site (Dent et al, 1997). These in vitro observations are supported by the in vivo observations made in Bcl-6-de®cient mice (Dent et al, 1997). Bcl-6-de®cient mice are characterized by a Th2 in¯ammatory disease of the heart and lungs.…”

“…Bcl-6 is a transcriptional repressor normally expressed in germinal center B cells and some T cells (Cattoretti et al, 1995;Seyfert et al, 1996). Although Bcl-6 does not resemble Stat6 structurally, Bcl-6 is capable of recognizing the Stat6-speci®c DNA binding site (Dent et al, 1997). When Bcl-6 is overexpressed it can block the ability of Stat6 to transactivate the CD23 promoter by presumably competing for the Stat6 binding site (Dent et al, 1997).…”

The t(2;3)(q21;q27) translocation in non-Hodgkin's lymphoma displays BCL6 mutations in the 5′ regulatory region and chromosomal breakpoints distant from the gene

“…The BCL6 gene encodes a POZ/Zinc ®nger transcription factor which functions as a sequence speci®c transcription repressor Chang et al, 1996;Seyfert 1996;Baron et al, 1997). The primary function of BCL6 appears to be regulation of germinal center (GC) development and T-cell directed immune response (Dent et al, 1997;Ye et al, 1997). Activating BCL6 rearrangements have been shown to result from chromosomal translocations with IG or other loci that alter BCL6 expression by promoter substitution, or from point mutations in the 5' regulatory region (Migliazza et al, 1995;Ye et al, 1995;Chen et al, 1998).…”

Nonrandom 4p13 rearrangements of the RhoH/TTF gene, encoding a GTP-binding protein, in non-Hodgkin's lymphoma and multiple myeloma

“…LAZ3 exerts its transcriptional repressing e ect by the recruitment of both the SMRT co-repressor (Dhordain et al, 1997) and a SMRT/mSIN3A/Histone deacetylase containing complex (Dhordain et al, 1998;Wong and Privalsky, 1998). The LAZ3 gene shows a speci®c and high expression in germinal-center (GC) B cells (Cattoretti et al, 1995;Bajalica-Lagerkrantz et al, 1997) and controls GC formation and Th2-type in¯ammation (Dent et al, 1997;Ye et al, 1997).…”