MUC1 is activated in a B-cell lymphoma by the t(1;14)(q21;q32) translocation and is rearranged and amplified in B-cell lymphoma subsets.

The band 1q21 is among the most common sites affected by chromosomal translocations in lymphoid, myeloid, epithelial, and sarcomatous lesions. In non-Hodgkin's lymphoma (NHL), translocations and duplications affecting this chromosomal site are frequently, but not exclusively, seen in association with primary abnormalities such as the t(14;18)(q32;q21) and t(8;14)(q24;q32) translocations, suggesting a role for 1q21 rearrangements in tumor progression. We report here the characterization and cloning of breakpoints in a case of extranodal ascitic B-cell lymphoma with a t(1;14)(q21;q32) translocation. The breakpoints on the der(1) and der(14) chromosomes were mapped by fluorescence in situ hybridization and Southern blot analysis and cloned using an IGHG (Cgamma) probe. The translocation linked the IGHG4 switch (Sgamma4) sequences of the productively rearranged allele to chromosome 1 sequences downstream of MUC1, leaving the MUC1 transcriptional unit intact. MUC1 was markedly overexpressed in the tumor at the mRNA and protein levels relative to lymphoma cell lines lacking a 1q21 rearrangement. Presumably, MUC1 transcription is aberrantly regulated by the IGHA (Calpha) 3' enhancer element retained on the same chromosome. Screening of a panel of B-cell lymphomas by Southern blot analysis identified a subset with a 3' MUC1 breakpoint and another with low-level amplification of MUC1. MUC-1 mucin has previously been shown to be frequently overexpressed in human epithelial cancers and to be associated with tumor progression and poor clinical outcome. Thus, MUC1 activation by chromosomal translocation, rearrangement, and amplification, identified here for the first time in NHL, is consistent with its suggested role in tumorigenesis. (Blood. 2000;95:2666-2671)

BCL8, a novel gene involved in translocations affecting band 15q11-13 in diffuse large-cell lymphoma.

Translocations affecting the chromosomal region 15q11-13 and various other partners are recurrent in diffuse large-cell lymphomas (DLCL). To identify the putative gene, here named BCL8, involved in these translocations we have cloned the breakpoint region from a DLCL patient with t(14;15)(q32;q11-13) and the corresponding germ-line region from chromosome 15. The genomic locus on chromosome 15 is clonally rearranged in about 4% of DLCL in agreement with the frequency of 15q11-13 translocations. A probe derived from the BCL8 locus on chromosome 15 detected a transcript in human testis and prostate, whereas no expression was found in spleen, thymus, and blood leukocytes. Analysis of the BCL8 cDNA clones isolated from human testis cDNA library showed that the BCL8 gene generates a major transcript of 2.6 kb and a less prominent 4.5-kb species due to differential polyadenylylation. By reverse transcription-PCR analysis of RNA extracted from frozen DLCL samples and lymphoma cell lines, BCL8 expression was detected in all patients carrying 15q11-13 abnormalities and in a fraction of randomly selected DLCL patients. These results suggest that the BCL8 gene is not normally expressed in lymphoid tissues, but its expression can be activated by chromosomal translocation or by other mechanisms in DLCL. Ectopic expression of BCL8 in a significant proportion of DLCL suggests an important role for this gene in the molecular pathogenesis of B cell lymphoma.