Analysis for transcriptional regulation of the BCL6 gene

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Rearrangements of the BCL6 gene have been frequently found in human B-cell lymphomas, as a result of reciprocal chromosomal translocation involving band 3q27. Chromosomal breaks preferentially occur within a 3-kb region containing the first exon and intron of thh BCL6 gene. Recent reports revealed that internal deletions or point mutations within this limited region are also common in B-cell lymphomas. These observations suggest that the structural alteration of the first exon-intron boundary region of the BCL6 gene, a putative regulatory region, may be crucial event in the development of B-cell lymphomas. To further understand the mechanism of the deregulated expression of BCL6 in lymphomas, we investigated the physiological function of this region in transcriptional regulation of the BCL6 gene.Through luciferase reporter assay using B-cell line Raji, we have identified two regions that negatively regulate BCL6 expression. One region designated as ES located within the first exon betw … More een nucleotides +472 and +543, and the other region designated as IS between +783 and +918 of the first intron. Consensus nucleotide sequence for a binding of BCL6 protein itself was found within the ES region. Subsequent electrophoretic mobility shift assay revealed an actual binding of BCL6 to the ES region. Co-transfection experiment using a BCL6 expression vector showed that transcription of the BCL6 gene was partly regulated by a negative feedback of the BCL6 gene product.Another negative regulatory region IS has been shown to have a silencer activity. The IS region is entirely included in the regions commonly deleted in B-cell lymphomas as well as in the parts where somatic hypermutations are found in both normal and neoplastic B-cells. Electrophoretic mobility shift assay showed that the nuclear proteins that specifically bind to this intronic silencer element are expressed in several hematopoietic cell lines.Taken together, the identified regions of the BCL6 gene contain negative regulatory elements and the structural alterations of these regions have potential roles in the deregulated expression of the BCL6 gene in B-cell lymphomas. Less