The BCL6 gene, encoding a POZ/Zinc finger protein which acts as a transcriptional repressor, is frequently altered at its 5' non-coding region by 3q27 chromosomal translocations in B-cell non-Hodgkin's lymphoma (NHL). BCL6 rearrangement is one of the most common genetic abnormalities in NHL. As a result of translocations, the regulatory region of the BCL6 gene is replaced by an heterologous reciprocal partner such as the immunoglobulin (IG) genes. Promotor substitution leads to deregulation of the BCL6 expression, which may be associated with lymphomagenesis. Recent studies have shown that the 5' non-coding region of the BCL6 gene is also subject to somatic hypermutation physiologically operating in germinal center (GC) B-cells in a similar pattern to that of the IG genes. There is little evidence to show that structural alterations of the BCL6 gene may be caused by mechanisms other than chromosomal translocations. To date, five cases with NHL exhibiting gross BCL6 deletions of the 1.5-2.4 kb have been reported. These deletions occurred in the same region as translocational breakpoints and the somatic hypermutations cluster, but independently of chromosomal rearrangements. The deletions overlapped at the 270 bp region and this region contains a putative protein-binding sequence which may play a role in the regulation of the BCL6 expression. Small separated deletions of 22-101 bp, which may also contain protein-binding sequences, were evident in another NHL case. In contrast to the TAL1 deletion in T-cell acute lymphoblastic leukemia (ALL), the BCL6 deletion is considered to be mediated by a mechanism other than aberrant activity of the IG recombinase. Internal deletion within the BCL6 gene is a recurrent molecular abnormality in B-cell NHL, which is sometimes indistinguishable from rearrangements by chromosomal translocations. At present, the mechanism of DNA recombination and its role in lymphomagenesis remain unknown.