Identification of heterologous translocation partner genes fused to the BCL6 gene in diffuse large B-cell lymphomas: 5′-RACE and LA – PCR analyses of biopsy samples

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Abstract
In order to elucidate the molecular mechanism(s) for BCL6 translocation, we identified translocational partner genes by subjecting clinical biopsy samples from patients with non-Hodgkin's lymphoma to 5′-rapid amplification of cDNA ends (5′-RACE). Sequence analysis of the 5′-RACE product revealed that the BCL6 gene was fused to the J segment of the immunoglobulin heavy chain (IgH) gene in about half of the cases, but in the other half, it was fused to heterologous partners, including the MHC class II transactivator (CIITA), pim-1, eukaryotic initiation factor 4AII (eif4AII), transferrin receptor (TFRR) and ikaros genes. Since analyses using genomic long and accurate (LA) – PCR revealed that the breakpoints in the partner gene were confined to the first intron or the second exon in all cases, the promoter and the first exon of the BCL6 gene were replaced by the promoter and the first or both the first and second exon of the partner gene. The breakpoint flanking sequences had no recombination signal sequences (RSSs) or chi sequences and were homologous with the switch region only when the BCL6 gene was fused to the IgH gene, suggesting that BCL6 translocation cannot be explained solely by mistakes of V(D)J, or chi-mediated or class-switch recombination, but rather another mechanism may also be required to explain the molecular mechanism for the promiscuous BCL6 translocation.