Breaking bad in the germinal center: how deregulation of BCL6 contributes to lymphomagenesis

•BCL6 maintains a delicate balance between survival and apoptosis in germinal center (GC) B cells. •BCL6 maintains promoters and enhancers in a poised state in GC and lymphoma cells. •BCL6 mechanism of action varies among cell types in the immune system. •BCL6 mechanism-specific targeting kills lymphomas without harming other tissues. The B cell lymphoma 6 (BCL6) transcriptional repressor is a master regulator of the germinal center (GC) B cell program, required for their unique proliferative and stress tolerant phenotype. Most B cell lymphomas arise from GC B cells and are dependent on the continued or deregulated expression of BCL6 to maintain their survival. The actions of BCL6 in B cells involve formation of distinct chromatin modifying complexes that silence specific promoter and enhancer networks, respectively. The same biochemical mechanisms are maintained in malignant lymphoma cells. Targeted inhibition of these BCL6 functions has emerged as the basis for rational design of lymphoma therapies and combinatorial regimens. In this review, we summarize recent advances on BCL6 mechanisms of action and the deregulation of its target gene networks in lymphoma. The B cell lymphoma 6 (BCL6) transcriptional repressor is a master regulator of the germinal center (GC) B cell program, required for their unique proliferative and stress tolerant phenotype. Most B cell lymphomas arise from GC B cells and are dependent on the continued or deregulated expression of BCL6 to maintain their survival. The actions of BCL6 in B cells involve formation of distinct chromatin modifying complexes that silence specific promoter and enhancer networks, respectively. The same biochemical mechanisms are maintained in malignant lymphoma cells. Targeted inhibition of these BCL6 functions has emerged as the basis for rational design of lymphoma therapies and combinatorial regimens. In this review, we summarize recent advances on BCL6 mechanisms of action and the deregulation of its target gene networks in lymphoma. a transcriptional repressor and member of the BTB/POZ zinc finger family of transcription factors. BCL6 was initially cloned from a translocation occurring on chromosome 3q27 in diffuse large B cell lymphoma (DLBCL). a transcriptional corepressor that interacts with BCL6 in GC B cells and lymphoma. BCOR forms a polycomb repression complex 1 (PRC1)-like complex containing the histone demethylase KDM2B, ubiquitin ligases RING1A and RING1B and other PRC1-related proteins a structural domain located at the N terminus of BCL6 that mediates BCL6 dimerization and nuclear localization. BCL6 BTB dimerization generates two identical and symmetrical lateral grooves at the interface between BTB monomers. These serve as docking sites for corepressor recruitment. GC B cells undergoing rapid division and somatic hypermutation of their immunoglobulin loci. Centroblasts form the dark zone of the GC. nondividing activated GC B cells that derive from centroblasts and migrate to the light zone of the GC where they test the affinity of their antibody receptors with help from FDCs and GC follicular helper T cells. sites within secondary lymphoid organs that emerge upon B cell activation and mount the generation of long-lived, high-affinity T cell dependent B cell responses. Within the GCs, B cells undergo clonal expansion, immunoglobulin somatic hypermutation, and class switch recombination, leading to antibody affinity maturation. small peptides designed to mimic the SMRT peptide sequence that directly interacts with the BCL6 dimer. These peptides bind to the BCL6 BTB domain and result in disruption of the interaction of BCL6 with BTB domain corepressors, derepression of BCL6 target genes, and lymphoma cell death. RI-BPIs display favorable pharmacokinetic properties and can fully eradicate established lymphomas in mouse models. homologous corepressor proteins that interact with many repressive transcription factors. The core SMRT/NCOR repression complex contains HDAC3, TBL1 (and/or its homolog TBLR1), and GPS2.