BCL6

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 Zin finger family domain), (2) a central RN2 region, and (3) another zinc finger at the C-terminal end.^[6] This structure is vital to BCL6’s function – an exon 7 skipping splice variant encodes a shorter form of the protein which lacks the first two zinc fingers of the DNA binding domain,^[7] for example.

Bcl-6 is a master transcription factor for the regulation of T follicular helper cells (T_FH 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 (T_FH cell).^[8] T_FH cells are vital to the generation of germinal centers in the follicles of secondary lymphoid organs, where B cells divide and help fight infections.^[5]

As a master transcription factor, BCL6 interacts with a variety of co-repressors and other proteins to influence the T cell lineage. BCL6 has been shown to modulate the STAT-dependent Interleukin 4 (IL-4) responses of B cells^{[citation needed]} and suppress the production of BCL2.^[6]

Importantly, Bcl-6 should only be expressed when there is an antigen present and further stimulation of the immune system is necessary, since BCL6 prevents cell death (apoptosis). Unchecked growth can lead to lymphomas. Normally, the action of BCL6 is negatively regulated by the gene PRDM1 encoding the transcription factor Blimp-1.^[9] 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.

BCL6 is currently considered a lineage-defining transcription factor in T_FH cell differentiation.^[10] Without the expression of BCL6, naïve CD4+ T helper cells will not turn into T_FH 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 T_FH cells. Signaling through the IL-6 receptor leads to T_FH cell differentiation, and in turn the expression of BCL6 in T_FH lineage-defined cells. BCL6 allows, through transcriptional regulation, unique cell markers to be expressed, resulting in an effective T_FH cell.^[10]

Transcriptional regulation of BCL6 is vast and complex, but many of the outcomes of BCL6’s transcriptional regulation on T_FH cells have been elucidated. T_FH 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 SAP^hi, CD200^hi and BTLA^hi on their cell surface in the newly formed germinal center. Additionally, BCL6 directly binds and suppresses genes that are downregulated in non-T_FH cells, including Ccr7, Selplg, and Gpr183, and other chemokine receptor targets.^[10]

BCL6 is found to be frequently translocated and hypermutated in diffuse large B cell lymphoma (DLBCL)^[11][12][13] 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.^[14]

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.^[6] Given its role as a master transcription regulator, many genetic and epigenetic changes can be responsible for B-cell lymphomas; these interacting proteins are likely a few of many that affect BCL6’s function.

Tracking BLC6 in B cells using immunohistochemical staining or enzyme-linked immunosorbent assay (ELISA) can be used to diagnose cancers and may indicate other illnesses as well. As mentioned previously, tracking BCL6 in tandem with BCL2 can lead to the diagnosis of B-cell lymphomas. More recently, it has been hypothesized that the presence of BCL6 in serum could be used to diagnose endometriosis due to an overactivation of BCL6 in endometriotic females,^[15][16] although this diagnostic method has not been found to work.^[17] Nonetheless, the understanding of BCL6 will likely continue to be used to diagnose diseases.

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.^[18]

BCL6 has been shown to interact with

• Nodular lymphocyte predominant Hodgkin's lymphoma
• Diffuse large B cell lymphoma

• BCL6+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human BCL6 genome location and BCL6 gene details page in the UCSC Genome Browser.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.