The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation

Abstract

Structural alterations of the promoter region of the BCL-6 proto-oncogene represent the most frequent genetic alteration associated with non-Hodgkin lymphoma, a malignancy often deriving from germinal-centre B cells. The BCL-6 gene encodes a zinc-finger transcriptional repressor normally expressed in both B cells and CD4+ T cells within germinal centres, but its precise function is unknown. We show that mice deficient in BCL-6 displayed normal B-cell, T-cell and lymphoid-organ development but have a selective defect in T-cell-dependent antibody responses. This defect included a complete lack of affinity maturation and was due to the inability of follicular B cells to proliferate and form germinal centres. In addition, BCL-6-deficient mice developed an inflammatory response in multiple organs characterized by infiltrations of eosinophils and IgE-bearing B lymphocytes typical of a Th2-mediated hyperimmune response. Thus, BCL-6 functions as a transcriptional switch that controls germinal centre formation and may also modulate specific T-cell-mediated responses. Altered expression of BCL-6 in lymphoma represents a deregulation of the pathway normally leading to B cell proliferation and germinal centre formation.

Analysis of MUM1/IRF4 Protein Expression Using Tissue Microarrays and Immunohistochemistry

“…Under the study conditions we describe, CD138 and VS38 were more effective and specific in detecting plasmacytic differentiation in tissue microarrays as well as in individually tested cases of LPL and MZL. Our findings of the immunoreactivity of CD138 and VS38 in LPL and MZL with and without plasmacytic differentiation are entirely in agreement with previous studies for these markers (24,25,27,28,(45)(46)(47)(48). Although careful morphologic correlation of consecutive sections in cases immunoreactive for all three markers revealed similar patterns of distribution of stained cells, MUM1 consistently stained a larger number of lesional cells than did CD138 or VS38.…”

Far from solved: A perspective on what we know about early mechanisms of left–right asymmetry

“…Like in frog (Hilton et al, 2007;Sakano et al, 2010), BCoR mutations randomize LR asymmetry in human embryos (Ng et al, 2004;Hilton et al, 2007), but this does not occur in mouse (Ye et al, 1997;Yoshida et al, 1999). The loss of brain asymmetry observed in mouse mutants with ciliary dyskinesia (Kawakami et al, 2008) is not observed in human patients (Kennedy et al, 1999;Tanaka et al, 1999;McManus et al, 2004;Afzelius and Stenram, 2006).…”

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

“…5'RACE analysis of the BCL6 transcripts was performed using the 5'RACE kit (GIBCO/BRL) following manufacturer's recommendations. The primers used for cDNA ampli®cation were as previously described (Ye et al, 1997), except that the reverse primer 567 (AGGGTT-GATCTCAGGATC) at exon 4 was also used for the ®nal ampli®cation. The ®nal PCR product was subcloned into PGEM-T (Promega) and sequenced.…”

“…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).…”