CHROMOSOMAL TRANSLOCATIONS CAUSE DEREGULATED BCL6 EXPRESSION BY PROMOTER SUBSTITUTION IN B-CELL LYMPHOMA

The BCL6 gene codes for a zinc-finger transcription factor and is invo lved in chromosomal rearrangements in 30-40% of diffuse large-cell lym phoma (DLCL), These rearrangements cluster within the 5' regulatory re gion of BCL6 spanning its first non-coding exon, To determine the func tional consequences of these alterations, we have analyzed the structu re of the rearranged BCL6 alleles and their corresponding RNA and prot ein species in two DLCL biopsies and one tumor cell line which carried the t(3;14)(q27;q32) translocation involving the BCL6 and immunoglobu lin heavy-chain (IgH) loci, In all three cases, the breakpoints were m apped within the IgH switch region and the BCL6 first intron, leading to the juxtaposition of part of the IgH locus upstream and in the same transcriptional orientation to the BCL6 coding exons, An analysis of cDNA clones showed that these recombinations generate chimeric IgH-BCL 6 transcripts which initiated from IgH germline transcript promoters ( I-mu or I(gamma)3), but retain a normal BCL6 coding domain, In the tum or cell line, the chimeric I(gamma)3-BCL6 allele, but not the germline BCL6 gene, was transcriptionally active and produced a normal BCL6 pr otein, These findings indicate that t(3;14) translocations alter BCL6 expression by promoter substitution and imply that the consequence of these alterations is the deregulated expression of a normal BCL6 prote in.