Bcl-6 (B-cell lymphoma 6) is aprotein that in humans is encoded by theBCL6gene. BCL6 is a master transcription factor for regulation ofT follicular helper cells (TFH cells) proliferation.[5] BCL6 has three evolutionary conserved structural domains.[6] The interaction of these domains withcorepressors allows forgerminal center development and leads toB cell proliferation.
Thedeletion of BCL6 is known to lead to failure of germinal center formation in the follicles of thelymph nodes, preventing B cells from undergoingsomatic hypermutation.[6]Mutations in BCL6 can lead toB cell lymphomas because it promotes unchecked B cell growth.[6] Clinically, BCL6 can be used to diagnose B cell lymphomas and is shown to be upregulated in a number of cancers.[6]
Bcl-6 is a master transcription factor for the regulation ofT follicular helper cells (TFH cells). Bcl-6 is expressed when the cytokinesIl-6 and/orIl-21 are recognized; these cytokines can be produced by antigen presenting cells (APCs:B cells,dendritic cells, ormacrophages) 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).[8] 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.[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-dependentInterleukin 4 (IL-4) responses ofB 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 genePRDM1 encoding the transcription factorBlimp-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 TFH cell differentiation.[10] Without the expression of BCL6, naïve CD4+ T helper cells will not turn into TFH cells. When a naïve CD4+ T cell binds toMHC class II and an antigen peptide on adendritic cell, asignaling cascade ensues in which some proliferating T cells become TFH cells. Signaling through theIL-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.[10]
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 upregulateCXCR5,IL-6R, andICOS 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 andBTLAhi on their cell surface in the newly formed germinal center. Additionally, BCL6 directly binds and suppresses genes that are downregulated in non-TFH cells, includingCcr7,Selplg, andGpr183, and other chemokine receptor targets.[10]
BCL6 is found to be frequently translocated and hypermutated indiffuse 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 onimmunohistochemical staining, revealing the presence ofBurkitt's lymphoma,follicular lymphoma and the nodular lymphocyte predominant subtype ofHodgkin's disease. It is often used together with antibodies toBcl-2 antigen to distinguishneoplastic 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-translationalphosphorylation can be affected by mutations inFBXO11. Finally, BCL6’s interaction with other mutated proteins, includingCREBBP,EP300, EZH2, andKM2TD, 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 usingimmunohistochemical staining orenzyme-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 diagnoseendometriosis 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]
^Ye BH, Lista F, Lo Coco F, Knowles DM, Offit K, Chaganti RS, et al. (October 1993). "Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma".Science.262 (5134):747–750.Bibcode:1993Sci...262..747Y.doi:10.1126/science.8235596.PMID8235596.
^Kerckaert JP, Deweindt C, Tilly H, Quief S, Lecocq G, Bastard C (September 1993). "LAZ3, a novel zinc-finger encoding gene, is disrupted by recurring chromosome 3q27 translocations in human lymphomas".Nature Genetics.5 (1):66–70.doi:10.1038/ng0993-66.PMID8220427.S2CID12575122.
^Chetty R, Cooper K, Gown AM (2016).Leong's manual of diagnostic antibodies for immunohistology (3rd ed.). Cambridge: Cambridge university press.ISBN978-1-107-07778-2.
Ueda C, Akasaka T, Ohno H (July 2002). "Non-immunoglobulin/BCL6 gene fusion in diffuse large B-cell lymphoma: prognostic implications".Leukemia & Lymphoma.43 (7):1375–1381.doi:10.1080/10428190290033305.PMID12389616.S2CID27096971.
Niu H (December 2002). "The proto-oncogene BCL-6 in normal and malignant B cell development".Hematological Oncology.20 (4):155–166.doi:10.1002/hon.689.PMID12469325.S2CID24245607.
Tokuhisa T (December 2002). "[A role for Bcl6 in immune memory development]".Tanpakushitsu Kakusan Koso. Protein, Nucleic Acid, Enzyme.47 (16 Suppl):2306–2312.PMID12518453.
Ohno H (April 2004). "Pathogenetic role of BCL6 translocation in B-cell non-Hodgkin's lymphoma".Histology and Histopathology.19 (2):637–650.doi:10.14670/HH-19.637.PMID15024721.
Pasqualucci L, Bereshchenko O, Niu H, Klein U, Basso K, Guglielmino R, et al. (2004). "Molecular pathogenesis of non-Hodgkin's lymphoma: the role of Bcl-6".Leukemia & Lymphoma.44 (Suppl 3): S5-12.doi:10.1080/10428190310001621588.PMID15202519.S2CID25565667.
Jardin F, Ruminy P, Bastard C, Tilly H (February 2007). "The BCL6 proto-oncogene: a leading role during germinal center development and lymphomagenesis".Pathologie-Biologie.55 (1):73–83.doi:10.1016/j.patbio.2006.04.001.PMID16815642.
