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.