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BCL6

BCL6

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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 to 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

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Structure

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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 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

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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[5] 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[6]. 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

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BCL6 is currently considered a lineage-defining transcription factor in TFH cell differentiation[7]. 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[7].

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[7].

Clinical Value

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Role in B Cell Lymphomas

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BCL6 is found to be frequently translocated and hypermutated in diffuse large B cell lymphoma (DLBCL)[8][9][10] 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[11].

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, MET2B and IFR2, 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 CREBP, EP300, EXH2, 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

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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, is 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[12][13], although this diagnostic method has not been found to work[14]. Nonetheless, the understanding of BCL6 will likely continue to be used to diagnose diseases.

Targeted Therapies

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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 are have been developed and tested in preclinical models, showing promise of anti-lymphoma activity[15].

Interactions

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BCOR,

BTLAhi[7]

Ccr7[7]

CD200hi[7]

C-jun,

CREBP[2]

CXCR5[7]

EP300[2]

EXH2[2]

Gpr183[7]

ICOS[7]

IFR2[2]

IRF4,

IL-6R[7]

KM2TD[2]

MET2B[2]

NCOR2,

SAPhi[7]

Selplg[7]

BCOR BTLA[16] Ccr7[16] CD200hi[16] C-jun CREBP[17] CXCR5[16] EP300[17] EXH2[17] Gpr183[16]
HDAC4, HDAC7A, HDAC5 ICOS[18] IFR2[19] IRF4, IL-6R[18] KM2TD[19] MET2B[2]
NCOR2 SAP[7] Selplg[7] SMRT T-bet ZBTB16 ZBTB7A

Bibliography

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  1. ^ a b A., Owen, Judith (2013). Kuby immunology. W.H. Freeman. ISBN 978-1-4292-1919-8. OCLC 820117219.{{cite book}}: CS1 maint: multiple names: authors list (link)
  2. ^ a b c d e f g h i j k l m n 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. doi:10.3389/fcell.2019.00272. ISSN 2296-634X.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  3. ^ Huang, Xin; Shen, Yulei; Liu, Miao; Bi, Chengfeng; Jiang, Chunsun; Iqbal, Javeed; McKeithan, Timothy W.; Chan, Wing C.; Ding, Shi-Jian; Fu, Kai (2012-7). "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. PMC 3388146. PMID 22609116. {{cite journal}}: Check date values in: |date= (help)
  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". Science. doi:10.1126/science.1176676. PMC 2857334. PMID 19628815.{{cite journal}}: CS1 maint: PMC format (link)
  5. ^ citation needed
  6. ^ Johnston, Robert J.; Poholek, Amanda C.; DiToro, Daniel; Yusuf, Isharat; Eto, Danelle; Barnett, Burton; Dent, Alexander L.; Craft, Joe; Crotty, Shane (2009-08-21). "Bcl6 and Blimp-1 Are Reciprocal and Antagonistic Regulators of T Follicular Helper Cell Differentiation". Science. doi:10.1126/science.1175870. PMC 2766560. PMID 19608860.{{cite journal}}: CS1 maint: PMC format (link)
  7. ^ a b c d e f g h i j k l m n Choi, Jinyong; Crotty, Shane (2021-04). "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. {{cite journal}}: Check date values in: |date= (help)
  8. ^ 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". Science. doi:10.1126/science.8235596.
  9. ^ Kerckaert, Jean-Pierre; Deweindt, Clotilde; Tilly, Hervé; Quief, Sabine; Lecocq, Gérard; Bastard, Christian (1993-09). "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. ISSN 1546-1718. {{cite journal}}: Check date values in: |date= (help)
  10. ^ Migliazza, A.; Martinotti, S.; Chen, W.; Fusco, C.; Ye, B. H.; Knowles, D. M.; Offit, K.; Chaganti, R. S.; Dalla-Favera, R. (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. PMC 40389. PMID 8618933.{{cite journal}}: CS1 maint: PMC format (link)
  11. ^ McCluggage, W. G.; Maxwell, P. (1999-07). <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. {{cite journal}}: Check date values in: |date= (help)
  12. ^ Yoo, Jung-Yoon; Kim, Tae Hoon; Fazleabas, Asgerally T.; Palomino, Wilder A.; Ahn, Soo Hyun; Tayade, Chandrakant; Schammel, David P.; Young, Steven L.; Jeong, Jae-Wook; Lessey, Bruce A. (2017-07-28). "KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance". Scientific Reports. 7 (1). doi:10.1038/s41598-017-04577-w. ISSN 2045-2322.
  13. ^ 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.
  14. ^ Sansone, Alison M.; Hisrich, Brooke V.; Young, R. Brandt; Abel, William F.; Bowens, Zachary; Blair, Bailey B.; Funkhouser, Avery T.; Schammel, David P.; Green, Lisa J.; Lessey, Bruce A.; Blenda, Anna V. (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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  15. ^ 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.
  16. ^ a b c d e Choi, Jinyong; Crotty, Shane (2021-04). "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. {{cite journal}}: Check date values in: |date= (help)
  17. ^ a b c 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. doi:10.3389/fcell.2019.00272. ISSN 2296-634X.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  18. ^ a b Choi, Jinyong; Crotty, Shane (2021-04). "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. {{cite journal}}: Check date values in: |date= (help)
  19. ^ a b 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. doi:10.3389/fcell.2019.00272. ISSN 2296-634X.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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