BCL6

BCL6, or B-cell lymphoma 6, is a transcriptional repressor protein encoded by the BCL6 gene in humans. It plays a central role in the formation and maintenance of germinal centers (GCs) in B cells and also functions in T follicular helper (Tfh) cells. The BCL6 protein contains an N-terminal BTB/POZ domain that mediates dimerization and recruitment of corepressor complexes, and a C-terminal array of zinc finger motifs that binds DNA. Through these interactions, BCL6 represses a broad set of target genes involved in DNA damage response, cell cycle arrest, differentiation, and plasma cell development, allowing GC B cells to proliferate and undergo somatic hypermutation and class-switch recombination.

Expression of BCL6 is highest in GC B cells and in Tfh cells; signaling through CD40 and cytokines such as IL-21 promotes its expression, while downregulation is required for plasma cell differentiation. BCL6 acts by recruiting corepressors such as SMRT, NCoR, and BCOR and by modulating histone deacetylation at target promoters.

In lymphoid malignancies, BCL6 is a proto-oncogene frequently deregulated by chromosomal translocations, amplifications, or mutations. Rearrangements involving BCL6 at 3q27 can place it under the influence of IgH enhancers, leading to overexpression in cancers such as diffuse large B-cell lymphoma and follicular lymphoma. BCL6 overexpression contributes to lymphomagenesis by maintaining GC B-cell programs and suppressing differentiation pathways; thus it is a target of therapeutic research. Knockout or functional inhibition of BCL6 impairs GC formation in mice, highlighting its essential role in humoral immunity.