Chromosomal translocations affecting the BCL-6proto-oncogene, which are the most common, specific genetic alteration found in diffuse large B-cell lymphomas (DLBCLs), were first identified by Dalla-Favera and coworkers. Targeted deletion of BCL-6revealed its critical physiologic role for the formation of the germinal center (GC) and the production of memory T cells. Signals emanating from pathways associated with lymphocytic differentiation, such as IgM engagement or CD40-CD40L interaction, down-regulate BCL-6 expression. The Bcl-6 protein, a transcriptional repressor that is expressed in the mature GC, suppresses genes involved in apoptosis, cell cycle arrest, and in lymphocytic mitogenesis and differentiation. These observations indicate that BCL-6 inhibits lymphocytic differentiation and, hence, BCL-6 deregulated expression in DLBCLs contributes to the maintenance of the undifferentiated lymphoma phenotype.
In addition to the chromosomal translocations activatingBCL-6 in DLBCLs, the BCL-6 locus is altered by somatic mutations that are intriguingly also found in normal GC B cells. While the genesis of these BCL-6 mutations, which cluster around the transcription initiation site, are associated with the normal somatic hypermutation mechanism responsible for immunoglobulin variable sequences, the significance of these mutations in lymphomagenesis has remained unclear. In this issue, Pasqualucci and coworkers (page 2914) report mutations of BCL-6, which are not found in the normal GC, that disrupt negative autoregulation ofBCL-6 in 40% of DLBCL cases. In particular, the 2 Bcl-6 DNA binding sites located in the noncoding exon 1 are mutated such that Bcl-6 protein is unable to bind the mutant sites. These observations are similar to those recently reported by Wang et al (Proc Natl Acad Sci U S A. 2002;99:15018-15023) supporting the hypothesis that lack of self-control by BCL-6 contributes to the genesis of DLBCLs.
