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Gene Review

BCL6  -  B-cell CLL/lymphoma 6

Homo sapiens

Synonyms: B-cell lymphoma 5 protein, B-cell lymphoma 6 protein, BCL-5, BCL-6, BCL5, ...
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Disease relevance of BCL6

  • Specific peptide interference reveals BCL6 transcriptional and oncogenic mechanisms in B-cell lymphoma cells [1].
  • BCL6 is frequently activated in non-Hodgkin's lymphoma, but its mechanism of action has remained unclear [2].
  • We report here that, in 22/30 (73%) DLCL and 7/15 (47%) follicular lymphoma (FL), but not in other tumor types, the BCL6 gene is also altered by multiple (1.4 x 10(-3) -1.6 x 10(-2) per bp), often biallelic, mutations clustering in its 5' noncoding region [3].
  • The BCL6 gene encodes a zinc-finger transcription factor and is altered by chromosomal arrangements in its 5' noncoding region in approximately 30% of diffuse large-cell lymphoma (DLCL) [3].
  • In contrast, high-growth fraction lymphomas are characterized by an enhanced proliferative activity, as a result of the deregulation of oncogenes with cell cycle regulatory functions, such as BCL6, in large B-cell lymphoma, or c-myc, in Burkitt lymphoma [4].

High impact information on BCL6

  • MTA3 is expressed in the same pattern in germinal centers as BCL-6 [5].
  • The transcriptional repressor BCL-6 regulates B lymphocyte cell fate during the germinal center reaction by preventing terminal differentiation of B lymphocytes into plasma cells until appropriate signals are received [5].
  • Remarkably, exogenous expression of BCL-6 in a plasma cell line leads, in an MTA3-dependent manner, to repression of plasma cell-specific transcripts, reactivation of the B cell transcriptional program, expression of B lymphocyte cell surface markers, and reprogramming of cell fate [5].
  • BCL-6 physically interacts with Mi-2/NuRD and this interaction is sensitive to BCL-6 acetylation status [5].
  • This indicates that these syndromes are likely to result from defects in alternative functions of BCOR, such as interactions with transcriptional partners other than BCL-6 [6].

Chemical compound and disease context of BCL6


Biological context of BCL6


Anatomical context of BCL6

  • We show that BCL6 expression also dramatically extends the replicative lifespan of primary human B cells in culture and induces cyclin D1 expression, indicating that BCL6 has a similar activity in lymphoid cells [2].
  • BCL6 efficiently immortalizes primary mouse embryonic fibroblasts and cooperates with RAS in oncogenic transformation [2].
  • BCL6 encodes a transcription factor that represses genes necessary for the terminal differentiation of lymphocytes within germinal centers, and the misregulated expression of this factor is strongly implicated in several types of B cell lymphoma [13].
  • The results suggest that BCL6 may directly control the ability of B cell to interact with T cells during normal GC development [12].
  • The BCL6 nuclear phosphoprotein is expressed in a variety of tissues and is up-regulated particularly in lymph node germinal centers [14].

Associations of BCL6 with chemical compounds

  • Meta-analysis demonstrated that the preferentially altered sequence motifs of BCL6 in PMBL were TA (p=0.002) and AT (p=0.0008) dinucleotides and TAT trinucleotides (p=0.001) [15].
  • Finally, ultrastructural analyses in UTA-L cells exposed to BrdU for various times reveal that replication progresses just around, but not within, BCL6 subdomains [16].
  • The antiproliferative effects of vorinostat are believed to be due to drug-induced accumulation of acetylated proteins, including the core nucleosomal histones and other proteins (e.g., BCL6, p53 and Hsp90) [17].
  • These results demonstrate for the first time that resveratrol inhibits a BCL6-linked pathway and suggest that loss of BCL6 expression may represent a key event underlying the anti-proliferative activities of resveratrol on LY8 cells [9].
  • In addition, a general and specific inhibitor of HDACs, trichostatin A, did not alleviate the HIC-1- and gammaFBP-B-mediated transcriptional repression, as previously shown for BCL-6 [18].

Physical interactions of BCL6

  • We have identified a 17 residue fragment from SMRT that binds to the BCL6 BTB domain, and determined the crystal structure of the complex to 2.2 A [13].
  • These differences may also explain why LRF interacts with BCL6 but not with PLZF [19].
  • The POZ domains of BCL-6 and several other POZ proteins interact with corepressors N-CoR and SMRT [20].
  • Here we report an alternative mechanism by which BCL6 controls the transcription of genes lacking a BCL6 binding site and show that this mechanism was required for the prevention of tumor suppressor p53-independent cell cycle arrest in germinal center B cells [21].
  • Strikingly, BCoR interacts selectively with the POZ domain of BCL-6 but not with eight other POZ proteins tested, including PLZF [20].

Enzymatic interactions of BCL6


Regulatory relationships of BCL6


Other interactions of BCL6

  • Immunohistochemistry reveals the anticipated inverse relationship between BCL6 and PDCD2 expression in human tonsil [14].
  • Alterations in 2p, 3q, 13, and 18q were not associated with N-MYC, BCL6, RB, or BCL2 alterations, respectively, suggesting that other genes may be the targets of these genetic abnormalities in MCLs [27].
  • Other amplifications also affected genes for which a pathogenetic role in pancreatic carcinoma has not been described, such as BCL10 and BCL6, two members of the BCL family [28].
  • SIRT1 and other NAD-dependent deacetylases have been implicated in control of cellular responses to stress and in tumorigenesis through deacetylation of important regulatory proteins, including p53 and the BCL6 oncoprotein [29].
  • Overexpression experiments showed that BCL6 and HDAC4, -5, or -7 are intermingled onto common nuclear substructures and form stable complexes [30].

Analytical, diagnostic and therapeutic context of BCL6


  1. Specific peptide interference reveals BCL6 transcriptional and oncogenic mechanisms in B-cell lymphoma cells. Polo, J.M., Dell'Oso, T., Ranuncolo, S.M., Cerchietti, L., Beck, D., Da Silva, G.F., Prive, G.G., Licht, J.D., Melnick, A. Nat. Med. (2004) [Pubmed]
  2. A senescence rescue screen identifies BCL6 as an inhibitor of anti-proliferative p19(ARF)-p53 signaling. Shvarts, A., Brummelkamp, T.R., Scheeren, F., Koh, E., Daley, G.Q., Spits, H., Bernards, R. Genes Dev. (2002) [Pubmed]
  3. Frequent somatic hypermutation of the 5' noncoding region of the BCL6 gene in B-cell lymphoma. Migliazza, A., Martinotti, S., Chen, W., Fusco, C., Ye, B.H., Knowles, D.M., Offit, K., Chaganti, R.S., Dalla-Favera, R. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  4. Cell cycle deregulation in B-cell lymphomas. Sánchez-Beato, M., Sánchez-Aguilera, A., Piris, M.A. Blood (2003) [Pubmed]
  5. MTA3 and the Mi-2/NuRD complex regulate cell fate during B lymphocyte differentiation. Fujita, N., Jaye, D.L., Geigerman, C., Akyildiz, A., Mooney, M.R., Boss, J.M., Wade, P.A. Cell (2004) [Pubmed]
  6. Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR. Ng, D., Thakker, N., Corcoran, C.M., Donnai, D., Perveen, R., Schneider, A., Hadley, D.W., Tifft, C., Zhang, L., Wilkie, A.O., van der Smagt, J.J., Gorlin, R.J., Burgess, S.M., Bardwell, V.J., Black, G.C., Biesecker, L.G. Nat. Genet. (2004) [Pubmed]
  7. BCL6 overexpression prevents increase in reactive oxygen species and inhibits apoptosis induced by chemotherapeutic reagents in B-cell lymphoma cells. Kurosu, T., Fukuda, T., Miki, T., Miura, O. Oncogene (2003) [Pubmed]
  8. Overexpressed BCL6 (LAZ3) oncoprotein triggers apoptosis, delays S phase progression and associates with replication foci. Albagli, O., Lantoine, D., Quief, S., Quignon, F., Englert, C., Kerckaert, J.P., Montarras, D., Pinset, C., Lindon, C. Oncogene (1999) [Pubmed]
  9. Resveratrol induces apoptosis in transformed follicular lymphoma OCI-LY8 cells: Evidence for a novel mechanism involving inhibition of BCL6 signaling. Faber, A.C., Chiles, T.C. Int. J. Oncol. (2006) [Pubmed]
  10. The human BCL6 transgene promotes the development of lymphomas in the mouse. Baron, B.W., Anastasi, J., Montag, A., Huo, D., Baron, R.M., Karrison, T., Thirman, M.J., Subudhi, S.K., Chin, R.K., Felsher, D.W., Fu, Y.X., McKeithan, T.W., Baron, J.M. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  11. Possible interaction between activator protein-1 and proto-oncogene B-cell lymphoma gene 6 in breast cancer patients resistant to tamoxifen. Altundag, K., Altundag, O., Gunduz, M., Arun, B. Med. Hypotheses (2004) [Pubmed]
  12. BCL6 controls the expression of the B7-1/CD80 costimulatory receptor in germinal center B cells. Niu, H., Cattoretti, G., Dalla-Favera, R. J. Exp. Med. (2003) [Pubmed]
  13. Mechanism of SMRT corepressor recruitment by the BCL6 BTB domain. Ahmad, K.F., Melnick, A., Lax, S., Bouchard, D., Liu, J., Kiang, C.L., Mayer, S., Takahashi, S., Licht, J.D., Privé, G.G. Mol. Cell (2003) [Pubmed]
  14. The human programmed cell death-2 (PDCD2) gene is a target of BCL6 repression: implications for a role of BCL6 in the down-regulation of apoptosis. Baron, B.W., Anastasi, J., Thirman, M.J., Furukawa, Y., Fears, S., Kim, D.C., Simone, F., Birkenbach, M., Montag, A., Sadhu, A., Zeleznik-Le, N., McKeithan, T.W. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  15. Primary mediastinal B-cell lymphoma: hypermutation of the BCL6 gene targets motifs different from those in diffuse large B-cell and follicular lymphomas. Malpeli, G., Barbi, S., Moore, P.S., Scardoni, M., Chilosi, M., Scarpa, A., Menestrina, F. Haematologica (2004) [Pubmed]
  16. DNA replication progresses on the periphery of nuclear aggregates formed by the BCL6 transcription factor. Albagli, O., Lindon, C., Lantoine, D., Quief, S., Puvion, E., Pinset, C., Puvion-Dutilleul, F. Mol. Cell. Biol. (2000) [Pubmed]
  17. Cancer biology: mechanism of antitumour action of vorinostat (suberoylanilide hydroxamic acid), a novel histone deacetylase inhibitor. Richon, V.M. Br. J. Cancer (2006) [Pubmed]
  18. 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. Deltour, S., Guerardel, C., Leprince, D. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  19. Structure of the POZ domain of human LRF, a master regulator of oncogenesis. Schubot, F.D., Tropea, J.E., Waugh, D.S. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  20. BCoR, a novel corepressor involved in BCL-6 repression. Huynh, K.D., Fischle, W., Verdin, E., Bardwell, V.J. Genes Dev. (2000) [Pubmed]
  21. BCL6 interacts with the transcription factor Miz-1 to suppress the cyclin-dependent kinase inhibitor p21 and cell cycle arrest in germinal center B cells. Phan, R.T., Saito, M., Basso, K., Niu, H., Dalla-Favera, R. Nat. Immunol. (2005) [Pubmed]
  22. BCL-6 is phosphorylated at multiple sites in its serine- and proline-clustered region by mitogen-activated protein kinase (MAPK) in vivo. Moriyama, M., Yamochi, T., Semba, K., Akiyama, T., Mori, S. Oncogene (1997) [Pubmed]
  23. BCL6 is regulated by p53 through a response element frequently disrupted in B-cell non-Hodgkin lymphoma. Margalit, O., Amram, H., Amariglio, N., Simon, A.J., Shaklai, S., Granot, G., Minsky, N., Shimoni, A., Harmelin, A., Givol, D., Shohat, M., Oren, M., Rechavi, G. Blood (2006) [Pubmed]
  24. Lineage-specific modulation of interleukin 4 signaling by interferon regulatory factor 4. Gupta, S., Jiang, M., Anthony, A., Pernis, A.B. J. Exp. Med. (1999) [Pubmed]
  25. The ARF tumor suppressor inhibits BCL6-mediated transcriptional repression. Suzuki, H., Kurita, M., Mizumoto, K., Moriyama, M., Aiso, S., Nishimoto, I., Matsuoka, M. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  26. Cloning and characterization of the human BAZF gene, a homologue of the BCL6 oncogene. Sakashita, C., Fukuda, T., Okabe, S., Kobayashi, H., Hirosawa, S., Tokuhisa, T., Miyasaka, N., Miura, O., Miki, T. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  27. Increased number of chromosomal imbalances and high-level DNA amplifications in mantle cell lymphoma are associated with blastoid variants. Beà, S., Ribas, M., Hernández, J.M., Bosch, F., Pinyol, M., Hernández, L., García, J.L., Flores, T., González, M., López-Guillermo, A., Piris, M.A., Cardesa, A., Montserrat, E., Miró, R., Campo, E. Blood (1999) [Pubmed]
  28. Genomic DNA-chip hybridization reveals a higher incidence of genomic amplifications in pancreatic cancer than conventional comparative genomic hybridization and leads to the identification of novel candidate genes. Holzmann, K., Kohlhammer, H., Schwaenen, C., Wessendorf, S., Kestler, H.A., Schwoerer, A., Rau, B., Radlwimmer, B., Döhner, H., Lichter, P., Gress, T., Bentz, M. Cancer Res. (2004) [Pubmed]
  29. Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes. Heltweg, B., Gatbonton, T., Schuler, A.D., Posakony, J., Li, H., Goehle, S., Kollipara, R., Depinho, R.A., Gu, Y., Simon, J.A., Bedalov, A. Cancer Res. (2006) [Pubmed]
  30. Class II histone deacetylases are directly recruited by BCL6 transcriptional repressor. Lemercier, C., Brocard, M.P., Puvion-Dutilleul, F., Kao, H.Y., Albagli, O., Khochbin, S. J. Biol. Chem. (2002) [Pubmed]
  31. Frequent occurrence of BCL6 rearrangements in nodular lymphocyte predominance Hodgkin lymphoma but not in classical Hodgkin lymphoma. Wlodarska, I., Nooyen, P., Maes, B., Martin-Subero, J.I., Siebert, R., Pauwels, P., De Wolf-Peeters, C., Hagemeijer, A. Blood (2003) [Pubmed]
  32. BCL6 gene translocation in follicular lymphoma: a harbinger of eventual transformation to diffuse aggressive lymphoma. Akasaka, T., Lossos, I.S., Levy, R. Blood (2003) [Pubmed]
  33. Large cleaved and immunoblastic lymphoma may represent two distinct clinicopathologic entities within the group of diffuse large B-cell lymphomas. De Paepe, P., Achten, R., Verhoef, G., Wlodarska, I., Stul, M., Vanhentenrijk, V., Praet, M., De Wolf-Peeters, C. J. Clin. Oncol. (2005) [Pubmed]
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