Biology:BCL6

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Short description: Transcription factor for converting Naive T cells to TFH


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Bcl-6 (B-cell lymphoma 6) is a protein that in humans is encoded by the BCL6 gene. BCL6 is a master transcription factor for regulation of T follicular helper cells (TFH cells) proliferation.[1] BCL6 has three evolutionary conserved structural domains.[2] The interaction of these domains with corepressors allows for germinal center development and leads to B cell proliferation.

The deletion of BCL6 is known to lead to failure of germinal center formation in the follicles of the lymph nodes, preventing B cells from undergoing somatic hypermutation.[2] Mutations in BCL6 can lead to B cell lymphomas because it promotes unchecked B cell growth.[2] Clinically, BCL6 can be used to diagnose B cell lymphomas and is shown to be upregulated in a number of cancers.[2]

Other BCL genes, including BCL2, BCL3, BCL5, BCL7A, BCL9, and BCL10, also have clinical significance in lymphoma.

Normal physiological function

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 Zin finger family domain), (2) a central RN2 region, and (3) another zinc finger at the C-terminal end.[2] 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,[3] 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).[4] 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.[1]

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.[2]

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.[5] 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.[6] 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.[6]

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.[6]

Clinical Value

Role in B Cell Lymphomas

BCL6 is found to be frequently translocated and hypermutated in diffuse large B cell lymphoma (DLBCL)[7][8][9] 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.[10][verification needed]

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.[2] 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.

Diagnostic Ability

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,[11][12] although this diagnostic method has not been found to work.[13] 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.[14]

Interactions

BCL6 has been shown to interact with


See also

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

References

  1. ↑ 1.0 1.1 A., Owen, Judith (2013). Kuby immunology. W.H. Freeman. ISBN 978-1-4292-1919-8. OCLC 820117219. http://worldcat.org/oclc/820117219. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 Yang, Haopeng; Green, Michael R. (2019-11-07). "Epigenetic Programing of B-Cell Lymphoma by BCL6 and Its Genetic Deregulation". Frontiers in Cell and Developmental Biology 7: 272. doi:10.3389/fcell.2019.00272. ISSN 2296-634X. PMID 31788471. 
  3. ↑ Huang, Xin; Shen, Yulei; Liu, Miao; Bi, Chengfeng; Jiang, Chunsun; Iqbal, Javeed; McKeithan, Timothy W.; Chan, Wing C. et al. (July 2012). "Quantitative Proteomics Reveals that miR-155 Regulates the PI3K-AKT Pathway in Diffuse Large B-Cell Lymphoma". The American Journal of Pathology 181 (1): 26–33. doi:10.1016/j.ajpath.2012.03.013. ISSN 0002-9440. PMID 22609116. 
  4. ↑ Nurieva, Roza I.; Chung, Yeonseok; Martinez, Gustavo J.; Yang, Xuexian O.; Tanaka, Shinya; Matskevitch, Tatyana D.; Wang, Yi-Hong; Dong, Chen (2009-08-21). "Bcl6 Mediates the Development of T Follicular Helper Cells" (in EN). Science 325 (5943): 1001–1005. doi:10.1126/science.1176676. PMID 19628815. Bibcode: 2009Sci...325.1001N. 
  5. ↑ Johnston, Robert J.; Poholek, Amanda C.; DiToro, Daniel; Yusuf, Isharat; Eto, Danelle; Barnett, Burton; Dent, Alexander L.; Craft, Joe et al. (2009-08-21). "Bcl6 and Blimp-1 Are Reciprocal and Antagonistic Regulators of T Follicular Helper Cell Differentiation" (in EN). Science 325 (5943): 1006–1010. doi:10.1126/science.1175870. PMID 19608860. Bibcode: 2009Sci...325.1006J. 
  6. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 Choi, Jinyong; Crotty, Shane (April 2021). "Bcl6-Mediated Transcriptional Regulation of Follicular Helper T cells (TFH)". Trends in Immunology 42 (4): 336–349. doi:10.1016/j.it.2021.02.002. ISSN 1471-4906. PMID 33663954. PMC 8021443. http://dx.doi.org/10.1016/j.it.2021.02.002. 
  7. ↑ Ye, Bihui H.; Lista, Florigio; Coco, Francesco Lo; Knowles, Daniel M.; Offit, Kenneth; Chaganti, R. S. K.; Dalla-Favera, Riccardo (1993-10-29). "Alterations of a Zinc Finger-Encoding Gene, BCL-6, in Diffuse Large-Cell Lymphoma" (in EN). Science 262 (5134): 747–750. doi:10.1126/science.8235596. PMID 8235596. Bibcode: 1993Sci...262..747Y. https://www.science.org/doi/abs/10.1126/science.8235596. 
  8. ↑ Kerckaert, Jean-Pierre; Deweindt, Clotilde; Tilly, Hervé; Quief, Sabine; Lecocq, Gérard; Bastard, Christian (September 1993). "LAZ3, a novel zinc–finger encoding gene, is disrupted by recurring chromosome 3q27 translocations in human lymphomas" (in en). Nature Genetics 5 (1): 66–70. doi:10.1038/ng0993-66. ISSN 1546-1718. PMID 8220427. https://www.nature.com/articles/ng0993-66. 
  9. ↑ Migliazza, A.; Martinotti, S.; Chen, W.; Fusco, C.; Ye, B. H.; Knowles, D. M.; Offit, K.; Chaganti, R. S. et al. (1995-12-19). "Frequent somatic hypermutation of the 5' noncoding region of the BCL6 gene in B-cell lymphoma.". Proceedings of the National Academy of Sciences 92 (26): 12520–12524. doi:10.1073/pnas.92.26.12520. ISSN 0027-8424. PMID 8618933. Bibcode: 1995PNAS...9212520M. 
  10. ↑ McCluggage, W. G.; Maxwell, P. (July 1999). <338::aid-path383>3.0.co;2-2 "Manual of diagnostic antibodies for immunohistology. Anthony S.-Y. Leong, Kum Cooper and F. Joel W.-M. Leong. Greenwich Medical Media Ltd., London, 1999. Distributed worldwide by Oxford University Press. No. of pages: 385. ISBN: 1 900151 316". The Journal of Pathology 188 (3): 338–339. doi:10.1002/(sici)1096-9896(199907)188:3<338::aid-path383>3.0.co;2-2. ISSN 0022-3417. http://dx.doi.org/10.1002/(sici)1096-9896(199907)188:3<338::aid-path383>3.0.co;2-2. 
  11. ↑ Yoo, Jung-Yoon; Kim, Tae Hoon; Fazleabas, Asgerally T.; Palomino, Wilder A.; Ahn, Soo Hyun; Tayade, Chandrakant; Schammel, David P.; Young, Steven L. et al. (2017-07-28). "KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance". Scientific Reports 7 (1): 6765. doi:10.1038/s41598-017-04577-w. ISSN 2045-2322. PMID 28754906. PMC 5533722. Bibcode: 2017NatSR...7.6765Y. http://dx.doi.org/10.1038/s41598-017-04577-w. 
  12. ↑ Evans-Hoeker, Emily; Lessey, Bruce A.; Jeong, Jae Wook; Savaris, Ricardo F.; Palomino, Wilder A.; Yuan, Lingwen; Schammel, David P.; Young, Steven L. (2016-05-24). "Endometrial BCL6 Overexpression in Eutopic Endometrium of Women With Endometriosis". Reproductive Sciences 23 (9): 1234–1241. doi:10.1177/1933719116649711. ISSN 1933-7191. PMID 27222232. PMC 5933165. http://dx.doi.org/10.1177/1933719116649711. 
  13. ↑ Sansone, Alison M.; Hisrich, Brooke V.; Young, R. Brandt; Abel, William F.; Bowens, Zachary; Blair, Bailey B.; Funkhouser, Avery T.; Schammel, David P. et al. (2021-09-28). "Evaluation of BCL6 and SIRT1 as Non-Invasive Diagnostic Markers of Endometriosis". Current Issues in Molecular Biology 43 (3): 1350–1360. doi:10.3390/cimb43030096. ISSN 1467-3045. PMID 34698105. 
  14. ↑ Leeman-Neill, Rebecca J; Bhagat, Govind (2018-01-04). "BCL6 as a therapeutic target for lymphoma". Expert Opinion on Therapeutic Targets 22 (2): 143–152. doi:10.1080/14728222.2018.1420782. ISSN 1472-8222. PMID 29262721. http://dx.doi.org/10.1080/14728222.2018.1420782. 
  15. ↑ 15.0 15.1 "BCoR, a novel corepressor involved in BCL-6 repression". Genes & Development 14 (14): 1810–23. July 2000. doi:10.1101/gad.14.14.1810. PMID 10898795. 
  16. ↑ "Repression of AP-1 function: a mechanism for the regulation of Blimp-1 expression and B lymphocyte differentiation by the B cell lymphoma-6 protooncogene". Journal of Immunology 169 (4): 1922–9. August 2002. doi:10.4049/jimmunol.169.4.1922. PMID 12165517. 
  17. ↑ 17.0 17.1 "Histone deacetylase associated with mSin3A mediates repression by the acute promyelocytic leukemia-associated PLZF protein". Oncogene 16 (19): 2549–56. May 1998. doi:10.1038/sj.onc.1202043. PMID 9627120. 
  18. ↑ 18.0 18.1 "Recruitment of SMRT/N-CoR-mSin3A-HDAC-repressing complexes is not a general mechanism for BTB/POZ transcriptional repressors: the case of HIC-1 and gammaFBP-B". Proceedings of the National Academy of Sciences of the United States of America 96 (26): 14831–6. December 1999. doi:10.1073/pnas.96.26.14831. PMID 10611298. Bibcode: 1999PNAS...9614831D. 
  19. ↑ 19.0 19.1 19.2 "Class II histone deacetylases are directly recruited by BCL6 transcriptional repressor". The Journal of Biological Chemistry 277 (24): 22045–52. June 2002. doi:10.1074/jbc.M201736200. PMID 11929873. https://hal.archives-ouvertes.fr/hal-00379714/document. 
  20. ↑ "Lineage-specific modulation of interleukin 4 signaling by interferon regulatory factor 4". The Journal of Experimental Medicine 190 (12): 1837–48. December 1999. doi:10.1084/jem.190.12.1837. PMID 10601358. 
  21. ↑ 21.0 21.1 "Components of the SMRT corepressor complex exhibit distinctive interactions with the POZ domain oncoproteins PLZF, PLZF-RARalpha, and BCL-6". The Journal of Biological Chemistry 273 (42): 27695–702. October 1998. doi:10.1074/jbc.273.42.27695. PMID 9765306. 
  22. ↑ "Novel BTB/POZ domain zinc-finger protein, LRF, is a potential target of the LAZ-3/BCL-6 oncogene". Oncogene 18 (2): 365–75. January 1999. doi:10.1038/sj.onc.1202332. PMID 9927193. 
  23. ↑ "The lineage-defining factors T-bet and Bcl-6 collaborate to regulate Th1 gene expression patterns". The Journal of Experimental Medicine 208 (5): 1001–13. May 2011. doi:10.1084/jem.20102144. PMID 21518797. 
  24. ↑ "Colocalization and heteromerization between the two human oncogene POZ/zinc finger proteins, LAZ3 (BCL6) and PLZF". Oncogene 19 (54): 6240–50. December 2000. doi:10.1038/sj.onc.1203976. PMID 11175338. 

Further reading

  • "Non-immunoglobulin/BCL6 gene fusion in diffuse large B-cell lymphoma: prognostic implications". Leukemia & Lymphoma 43 (7): 1375–81. July 2002. doi:10.1080/10428190290033305. PMID 12389616. 
  • "The proto-oncogene BCL-6 in normal and malignant B cell development". Hematological Oncology 20 (4): 155–66. December 2002. doi:10.1002/hon.689. PMID 12469325. 
  • "[A role for Bcl6 in immune memory development]". Tanpakushitsu Kakusan Koso. Protein, Nucleic Acid, Enzyme 47 (16 Suppl): 2306–12. December 2002. PMID 12518453. 
  • "Pathogenetic role of BCL6 translocation in B-cell non-Hodgkin's lymphoma". Histology and Histopathology 19 (2): 637–50. April 2004. PMID 15024721. 
  • "Molecular pathogenesis of non-Hodgkin's lymphoma: the role of Bcl-6". Leukemia & Lymphoma 44 (Suppl 3): S5–12. 2004. doi:10.1080/10428190310001621588. PMID 15202519. 
  • "The BCL6 proto-oncogene: a leading role during germinal center development and lymphomagenesis". Pathologie-Biologie 55 (1): 73–83. February 2007. doi:10.1016/j.patbio.2006.04.001. PMID 16815642. 

External links

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



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