A gene, bcl-3, is found on chromosome 19 adjacent to the breakpoints in the translocation t(14;19)(q32;q13.1), which occurs in some cases of chronic lymphocytic leukemia. Sequence analysis of the human bcl-3 gene predicts a protein containing seven tandem copies of the SWI6/cdc10 motif. This motif was previously identified in yeast genes that regulate events at the start of the cell cycle and in invertebrate transmembrane proteins involved in cell differentiation pathways. Expression of bcl-3 in normal blood cells increases markedly following mitogenic stimulation, and leukemic cells with the translocation show much greater expression than controls. These results suggest that bcl-3 is a proto-oncogene that may contribute to leukemogenesis when abnormally expressed.