The t(14;18) chromosomal translocation of human follicular lymphoma recombines the candidate transforming gene bcl-2, located at 18q21, with the immunoglobulin (Ig) H-chain joining region (JH) at 14q32. To elucidate the consequences of this translocation, we cloned bcl-2 cDNAs from a pre-B cell line (Nall-1) and a t(14;18) lymphoma cell line (SU-DHL-6) and compared these sequences with their genomic counterparts. These studies revealed the complexity of bcl-2 gene expression in which six potential polyadenylation signals in exon 3 and two different 5' exons (exons 1 and 2) and promoters are alternatively used to generate different sized bcl-2 mRNAs. A single open reading frame (ORF), at the junction of exons 2 and 3, predicts a 239 amino acid, 26 kD protein. Most chromosome 18 breakpoints cluster within a 150 bp region of exon 3. In SU-DHL-6 the t(14;18) translocation juxtaposes a truncated bcl-2 gene with J6 in a tail-to-head configuration, resulting in the deregulated expression of chimeric bcl-2/Ig transcripts. Importantly, the SU-DHL-6 bcl-2 cDNA also contained several point mutations in the ORF, two of which altered the primary amino acid sequence. The deregulated expression of an altered bcl-2 gene may play a critical role in the disordered growth and differentiation of follicular B cell lymphoma.