BCL6

Structure The protein encoded by the BCL6 gene is a zinc finger transcription factor that has three evolutionarily conserved domains. BCL6 contains a (1) N-terminal BTB/POZ domain (Broad-complex, Tramtrack and Brick-a-brac/Pox virus and Zinc finger family domain), (2) a central RN2 region, and (3) another zinc finger at the C-terminal end. for example. Function Bcl-6 is a master transcription factor for the regulation of T follicular helper cells (TFH cells). Bcl-6 is expressed when the cytokines Il-6 and/or Il-21 are recognized; these cytokines can be produced by antigen presenting cells (APCs: B cells, dendritic cells, or macrophages) when activated. This occurs when a naïve T helper cell recognizes antigen and needs to migrate to the follicle as a T follicular helper cell (TFH cell). TFH cells are vital to the generation of germinal centers in the follicles of secondary lymphoid organs, where B cells divide and help fight infections. The antagonistic effect with Blimp-1 is a powerful role of BCL6, because it shuts off the normal pathway of differentiation toward other cell types. == Differentiation of TFH Cells ==

BCL6 is currently considered a lineage-defining transcription factor in TFH cell differentiation. Without the expression of BCL6, naïve CD4+ T helper cells will not turn into TFH cells. When a naïve CD4+ T cell binds to MHC class II and an antigen peptide on a dendritic cell, a signaling cascade ensues in which some proliferating T cells become TFH cells. Signaling through the IL-6 receptor leads to TFH cell differentiation, and in turn the expression of BCL6 in TFH lineage-defined cells. BCL6 allows, through transcriptional regulation, unique cell markers to be expressed, resulting in an effective TFH cell. Transcriptional regulation of BCL6 is vast and complex, but many of the outcomes of BCL6’s transcriptional regulation on TFH cells have been elucidated. TFH cells upregulate CXCR5, IL-6R, and ICOS during their migration to the germinal center. After interacting with a B cell presenting the cognate antigen in the follicle, they also upregulate SAPhi, CD200hi and BTLAhi on their cell surface in the newly formed germinal center. Additionally, BCL6 directly binds and suppresses genes that are downregulated in non-TFH cells, including Ccr7, Selplg, and Gpr183, and other chemokine receptor targets. == Clinical Value ==

Role in B Cell Lymphomas BCL6 is found to be frequently translocated and hypermutated in diffuse large B cell lymphoma (DLBCL) and contributes to the pathogenesis of DLBCL. BCL6 is exclusively present in the B-cells of both healthy and neoplastic (cancerous) germinal centers. This allows lymphoma’s to be diagnosed based on immunohistochemical staining, revealing the presence of Burkitt's lymphoma, follicular lymphoma and the nodular lymphocyte predominant subtype of Hodgkin's disease. It is often used together with antibodies to Bcl-2 antigen to distinguish neoplastic follicles from those found in benign hyperplasia, for which Bcl-2 is negative. Many different changes to BCL6 can lead to inhibited activity and are known to be linked with B-cell lymphomas, including direct effects (mutation and post-translational effects) as well as indirect effects (imbalanced interactions with other mutated proteins). Mutations to the transcription factors for BCL6, MEF2B and IRF8, are common in direct transcriptional changes that cause DLBCL. Additionally, post-translational phosphorylation can be affected by mutations in FBXO11. Finally, BCL6’s interaction with other mutated proteins, including CREBBP, EP300, EZH2, and KM2TD, can also lead to B-cell lymphomas. although this diagnostic method has not been found to work. Nonetheless, the understanding of BCL6 will likely continue to be used to diagnose diseases. Targeted Therapies Given BCL6’s role in B-cell lymphomas, it has been suggested as a therapeutic target for cancer treatment. Targeting BCL6 in cancer patients should lead to the deletion of BCL6 in tumor cells. Peptidomimetics, small molecules, and natural compounds have been developed and tested in preclinical models, showing promise of anti-lymphoma activity. == Interactions ==

BCL6 has been shown to interact with • BCOR, • CREBBP, • HDAC4, • ICOS, • IL-6R, • SAP, • T-bet, • ZBTB16 == See also ==