The Bcl6 gene encodes a zinc-finger transcription factor and is altered by chromosomal rearrangements in its 5' non-coding region in approximately 30% of diffuse large-cell lymphoma (DLCL). In addition, the 5' non-coding region of Bcl6 is targeted by somatic hypermutation in normal germinal center (GC) B cells and in GC-derived B cell non-Hodgkin lymphoma (B-NHL). The general goal of this project will be to investigate the role of Bcl6 hypermutation in B-NHL pathogenesis. In particular, the following specific lines of investigations will be pursued: 1) Functional consequences of Bcl6 hypermutation; we will investigate the role of Bcl6 mutations on the regulation of Bcl6 expression by determining whether mutations i) affect CD40-mediated Bcl6 downregulation; ii) induce an increased sensitivity to STAT6-mediated IL4 signaling; 2) Role of Bcl6 mutation in lymphomagenesis; transgenic mice carrying NHL-derived mutant Bcl6 alleles will be constructed and examined for the effects of mutations on i) B cell lineage development, ii) tumor development; 3) Examine the role of germinal centers and IgV somatic hypermutation in lymphomagenesis; we will attempt to determine whether the presence of germinal center and/or somatic hypermutation are required for lymphomagenesis using a transgenic mouse model generated by crossing lymphoma prone mice (lambda-myc) with mice that are unable to either form GC (Bcl6delta/delta mice) or undergo somatic hypermutation (AID-/- mice).
