Skip to main content
Log in

Common mechanisms for the regulation of B cell differentiation and transformation by the transcriptional repressor protein BCL-6

  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

The BCL-6 transcriptional repressor protein is a critical regulator of normal B cell differentiation and BCL-6 has recently been shown to act as an oncogene in several mouse model systems. The molecular pathways by which BCL-6 regulates B cell differentiation and also promotes the transformation of primary B cells are undoubtedly related; however, these pathways are poorly understood. The commonly accepted model for BCL-6 function in B cells is that BCL-6 inhibits the terminal differentiation of activated B cells into plasma cells and that deregulation of BCL-6 expression leads to an inhibition of terminal differentiation and continued proliferation. BCL-6 induces a germinal-center phenotype in primary B cells by unknown mechanisms, and can reverse the terminal differentiation of plasma cell tumor lines. BCL-6 can promote the immortalization of primary B cells and can augment telomerase activity. The role of the vast majority of BCL-6 target genes and interacting proteins in normal B cell differentiation and B cell transformation is essentially unresolved and is an important area for future investigation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Onizuka T, Moriyama M, Yamochi T, et al: BCL-6 gene product, a 92- to 98-kD nuclear phosphoprotein, is highly expressed in germinal center B cells and their neoplastic counterparts. Blood 1995; 86(1): 28–37.

    PubMed  CAS  Google Scholar 

  2. Cattoretti G, Chang CC, Cechova K, et al: BCL-6 protein is expressed in germinal-center B cells. Blood 1995; 86(1): 45–53.

    PubMed  CAS  Google Scholar 

  3. MacLennan IC: Germinal centers. Annu Rev Immunol 1994; 12: 117–139.

    Article  PubMed  CAS  Google Scholar 

  4. Ozaki K, Spolski R, Ettinger R, et al: Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J Immunol 2004; 173(9): 5361–5371.

    PubMed  CAS  Google Scholar 

  5. Arguni E, Arima M, Tsuruoka N, et al: JunD/AP-1 and STAT3 are the major enhancer molecules for high Bcl6 expression in germinal center B cells. Int Immunol 2006; 18(7): 1079–1089.

    Article  PubMed  CAS  Google Scholar 

  6. Allman D, Jain A, Dent A, et al: BCL-6 expression during B-cell activation. Blood 1996; 87(12): 5257–5268.

    PubMed  CAS  Google Scholar 

  7. Lee SC, Bottaro A, Chen L, Insel RA: Mad1 is a transcriptional repressor of Bcl-6. Mol Immunol 2006; 43(12): 1965–1971.

    Article  PubMed  CAS  Google Scholar 

  8. Calame KL, Lin KI, Tunyaplin C: Regulatory mechanisms that determine the development and function of plasma cells. Annu Rev Immunol 2003; 21: 205–230.

    Article  PubMed  CAS  Google Scholar 

  9. Pasqualucci L, Migliazza A, Basso K, et al: Mutations of the BCL6 proto-oncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma. Blood 2003; 101: 2914–2923.

    Article  PubMed  CAS  Google Scholar 

  10. Wang X, Li Z, Naganuma A, Ye BH: Negative autoregulation of BCL-6 is bypassed by genetic alterations in diffuse large B cell lymphomas. Proc Natl Acad Sci USA 2002; 99(23): 15018–15023.

    Article  PubMed  CAS  Google Scholar 

  11. Fujita N, Jaye DL, Geigerman C, et al: MTA3 and the Mi-2/NuRD complex regulate cell fate during B lymphocyte differentiation. Cell 2004; 119(1): 75–86.

    Article  PubMed  CAS  Google Scholar 

  12. Fukuda T, Yoshida T, Okada S, et al: Disruption of the Bcl6 gene results in an impaired germinal center formation. J Exp Med 1997; 186(3): 439–448.

    Article  PubMed  CAS  Google Scholar 

  13. Toney LM, Cattoretti G, Graf JA, et al: BCL-6 regulates chemokine gene transcription in macrophages. Nat Immunol 2000; 1(3): 214–220.

    Article  PubMed  CAS  Google Scholar 

  14. Staudt LM, Dent AL, Shaffer AL, Yu X: Regulation of lymphocyte cell fate decisions and lymphomagenesis by BCL-6. Int Rev Immunol 1999; 18(4): 381–403.

    PubMed  CAS  Google Scholar 

  15. Ye BH, Lista F, Lo Coco F, et al: Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. Science 1993; 262(5134): 747–750.

    Article  PubMed  CAS  Google Scholar 

  16. Ye BH, Chaganti S, Chang CC, et al: Chromosomal translocations cause deregulated BCL6 expression by promoter substitution in B cell lymphoma. EMBO J 1995; 14(24): 6209–6217.

    PubMed  CAS  Google Scholar 

  17. Niu H: The proto-oncogene BCL-6 in normal and malignant B cell development. Hematol Oncol 2002; 20(4): 155–166.

    Article  PubMed  Google Scholar 

  18. Dent AL, Vasanwala FH, Toney LM: Regulation of gene expression by the proto-oncogene BCL-6. Crit Rev Oncol Hematol 2002; 41(1): 1–9.

    Article  PubMed  Google Scholar 

  19. Shaffer AL, Yu X, He Y, et al: BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity 2000; 13(2): 199–212.

    Article  PubMed  CAS  Google Scholar 

  20. Phan RT, Saito M, Basso K, et al: 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. Nat Immunol 2005; 6(10): 1054–1060.

    Article  PubMed  CAS  Google Scholar 

  21. Reljic R, Wagner SD, Peakman LJ, Fearon DT: Suppression of signal transducer and activator of transcription 3-dependent B lymphocyte terminal differentiation by BCL-6. J Exp Med 2000; 192(12): 1841–1848.

    Article  PubMed  CAS  Google Scholar 

  22. Shaffer AL, Lin KI, Kuo TC, et al: Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 2002; 17(1): 51–62.

    Article  PubMed  CAS  Google Scholar 

  23. Shapiro-Shelef M, Lin KI, McHeyzer-Williams LJ, et al: Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity 2003; 19(4): 607–620.

    Article  PubMed  CAS  Google Scholar 

  24. Baron BW, Anastasi J, Thirman MJ, et al: 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. Proc Natl Acad Sci USA 2002; 99(5): 2860–2865.

    Article  PubMed  CAS  Google Scholar 

  25. Phan RT, Dalla-Favera R: The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature 2004; 432(7017): 635–639.

    Article  PubMed  CAS  Google Scholar 

  26. Kusam S, Vasanwala FH, Dent AL: Transcriptional repressor BCL-6 immortalizes germinal center-like B cells in the absence of p53 function. Oncogene 2004; 23(3): 839–844.

    Article  PubMed  CAS  Google Scholar 

  27. Miles RR, Crockett DK, Lim MS, Elenitoba-Johnson KS: Analysis of BCL6-interacting proteins by tandem mass spectrometry. Mol Cell Proteomics 2005; 4(12): 1898–1909.

    Article  PubMed  CAS  Google Scholar 

  28. Vasanwala FH, Kusam S, Toney LM, Dent AL: 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. J Immunol 2002; 169(4): 1922–1929.

    PubMed  CAS  Google Scholar 

  29. Huynh KD, Bardwell VJ: The BCL-6 POZ domain and other POZ domains interact with the co-repressors N-CoR and SMRT. Oncogene 1998; 17(19): 2473–2484.

    Article  PubMed  CAS  Google Scholar 

  30. Huynh KD, Fischle W, Verdin E, Bardwell VJ: BCoR, a novel corepressor involved in BCL-6 repression. Genes Dev 2000; 14(14): 1810–1823.

    PubMed  CAS  Google Scholar 

  31. Ohkubo Y, Arima M, Arguni E, et al: A role for c-fos/activator protein 1 in B lymphocyte terminal differentiation. J Immunol 2005; 174(12): 7703–7710.

    PubMed  CAS  Google Scholar 

  32. Dent AL, Shaffer AL, Yu X, et al: Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science 1997; 276(5312): 589–592.

    Article  PubMed  CAS  Google Scholar 

  33. Ye BH, Cattoretti G, Shen Q, et al: The BCL-6 protooncogene controls germinal-centre formation and Th2-type inflammation. Nat Genet 1997; 16(2): 161–170.

    Article  PubMed  CAS  Google Scholar 

  34. Tunyaplin C, Shaffer AL, Angelin-Duclos CD, et al: Direct repression of prdm1 by Bcl-6 inhibits plasmacytic differentiation. J Immunol 2004; 173(2): 1158–1165.

    PubMed  CAS  Google Scholar 

  35. Baron BW, Anastasi J, Montag A, et al: The human BCL6 transgene promotes the development of lymphomas in the mouse. Proc Natl Acad Sci USA 2004; 101(39): 14198–14203.

    Article  PubMed  CAS  Google Scholar 

  36. Cattoretti G, Pasqualucci L, Ballon G, et al: Deregulated BCL6 expression recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice. Cancer Cell 2005; 7(5): 445–455.

    Article  PubMed  CAS  Google Scholar 

  37. Polo JM, Dell'Oso T, Ranuncolo SM, et al: Specific peptide interference reveals BCL6 transcriptional and oncogenic mechanisms in B-cell lymphoma cells. Nat Med 2004; 10(12): 1329–1335.

    Article  PubMed  CAS  Google Scholar 

  38. Clodi K, Asgary Z, Zhao S, et al: Coexpression of CD40 and CD40 ligand in B-cell lymphoma cells. Br J Haematol 1998; 103(1): 270–275.

    Article  PubMed  CAS  Google Scholar 

  39. Pham LV, Tamayo AT, Yoshimura LC, et al: A CD40 signalosome anchored in lipid rafts leads to constitutive activation of NF-kappaB and autonomous cell growth in B cell lymphomas. Immunity 2002; 16(1): 37–50.

    Article  PubMed  CAS  Google Scholar 

  40. Pham LV, Tamayo AT, Yoshimura LC, et al: Constitutive NF-{kappa}B and NFAT activation in aggressive B cell lymphomas synergistically activates the CD154 gene and maintains lymphoma cell survival. Blood 2005; 106(12): 3940–3947.

    Article  PubMed  CAS  Google Scholar 

  41. Sharpless NE, DePinho RA: Telomeres, stem cells, senescence, and cancer. J Clin Invest 2004; 113(2): 160–168.

    Article  PubMed  CAS  Google Scholar 

  42. Klingelhutz AJ: The roles of telomeres and telomerase in cellular immortalization and the development of cancer. Anticancer Res 1999; 19(6A): 4823–4830.

    PubMed  CAS  Google Scholar 

  43. Hu BT, Insel RA: Up-regulation of telomerase in human B lymphocytes occurs independently of cellular proliferation and with expression of the telomerase catalytic subunit. Eur J Immunol 1999; 29(11): 3745–3753.

    Article  PubMed  CAS  Google Scholar 

  44. Norrback KF, Dahlenborg K, Carlsson R, Roos G: Telomerase activation in normal B lymphocytes and non-Hodgkin's lymphomas. Blood 1996; 88(1): 222–229.

    PubMed  CAS  Google Scholar 

  45. Hodes RJ, Hathcock KS, Weng NP: Telomeres in T and B cells. Nat Rev Immunol 2002; 2(9): 699–706.

    Article  PubMed  CAS  Google Scholar 

  46. Hu BT, Lee SC, Marin E, et al: Telomerase is up-regulated in human germinal center B cells in vivo and can be re-expressed in memory B cells activated in vitro. J Immunol 1997; 159(3): 1068–1071.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kusam, S., Dent, A. Common mechanisms for the regulation of B cell differentiation and transformation by the transcriptional repressor protein BCL-6. Immunol Res 37, 177–186 (2007). https://doi.org/10.1007/BF02697368

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02697368

Key words

Navigation