Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Lymphoma

Follicular dendritic cell-induced microRNA-mediated upregulation of PRDM1 and downregulation of BCL-6 in non-Hodgkin's B-cell lymphomas

Abstract

B-cell lymphoma 6 (BCL6) and PR domain containing 1 (PRDM1) are considered as master regulators for germinal center (GC) formation and terminal B-cell differentiation. Dysregulation of BCL6 and PRDM1 has been associated with lymphomagenesis. Here, we show for the first time that direct cell–cell contact between follicular dendritic cells (FDC) and B-lymphocytes, by influencing the expression of a set of microRNAs (miRNAs), regulates the expression of BCL6 and PRDM1. We identify that, on cell adhesion to FDC, FDC induces upregulation of PRDM1 expression through downregulation of miR-9 and let-7 families and induces downregulation of BCL-6 through upregulation of miR-30 family in B-lymphocytes and lymphoma cells. We further demonstrate that the miR-30 family directly controls BCL-6 expression and miR-9-1 and let-7a directly control PRDM-1 expression through targeting their 3′UTR, mediating the FDC effect. Our studies define a novel regulatory mechanism in which the FDC, through induction of miRNAs in B-lymphocytes, orchestrates the regulation of transcription factors, promotes germinal center B-cell survival and differentiation. Dysregulation of miRNAs may interfere with B-cell survival and maturation, thus representing a novel molecular mechanism, as well as a potential therapeutic target in B-cell lymphomas.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Klein U, Dalla-Favera R . Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol 2008; 8: 22–33.

    Article  CAS  PubMed  Google Scholar 

  2. Shaffer AL, Rosenwald A, Staudt LM . Lymphoid malignancies: the dark side of B-cell differentiation. Nat Rev Immunol 2002; 2: 920–932.

    Article  CAS  PubMed  Google Scholar 

  3. Park CS, Choi YS . How do follicular dendritic cells interact intimately with B cells in the germinal centre? Immunology 2005; 114: 2–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Visone R, Croce CM . MiRNAs and cancer. Am J Pathol 2009; 174: 1131–1138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Croce CM . MicroRNAs and lymphomas. Ann Oncol 2008; 19 (Suppl 4): iv39–iv40.

    PubMed  Google Scholar 

  6. Fabbri M, Croce CM, Calin GA . MicroRNAs in the ontogeny of leukemias and lymphomas. Leuk Lymphoma 2009; 50: 160–170.

    Article  CAS  PubMed  Google Scholar 

  7. Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, Xue Y et al. Regulation of the germinal center response by microRNA-155. Science 2007; 316: 604–608.

    Article  CAS  PubMed  Google Scholar 

  8. Teng G, Hakimpour P, Landgraf P, Rice A, Tuschl T, Casellas R et al. MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase. Immunity 2008; 28: 621–629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Costinean S, Sandhu SK, Pedersen IM, Tili E, Trotta R, Perrotti D et al. Src homology 2 domain-containing inositol-5-phosphatase and CCAAT enhancer-binding protein beta are targeted by miR-155 in B cells of Emicro-MiR-155 transgenic mice. Blood 2009; 114: 1374–1382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Kim HS, Zhang X, Choi YS . Activation and proliferation of follicular dendritic cell-like cells by activated T lymphocytes. J Immunol 1994; 153: 2951–2961.

    CAS  PubMed  Google Scholar 

  12. Choe J, Kim HS, Armitage RJ, Choi YS . The functional role of B cell antigen receptor stimulation and IL-4 in the generation of human memory B cells from germinal center B cells. J Immunol 1997; 159: 3757–3766.

    CAS  PubMed  Google Scholar 

  13. Choe J, Choi YS . IL-10 interrupts memory B cell expansion in the germinal center by inducing differentiation into plasma cells. Eur J Immunol 1998; 28: 508–515.

    Article  CAS  PubMed  Google Scholar 

  14. Nie K, Gomez M, Landgraf P, Garcia JF, Liu Y, Tan LH et al. MicroRNA-mediated down-regulation of PRDM1/Blimp-1 in Hodgkin/Reed-Sternberg cells: a potential pathogenetic lesion in Hodgkin lymphomas. Am J Pathol 2008; 173: 242–252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cattoretti G, Chang CC, Cechova K, Zhang J, Ye BH, Falini B et al. BCL-6 protein is expressed in germinal-center B cells. Blood 1995; 86: 45–53.

    CAS  PubMed  Google Scholar 

  16. Parekh S, Polo JM, Shaknovich R, Juszczynski P, Lev P, Ranuncolo SM et al. BCL6 programs lymphoma cells for survival and differentiation through distinct biochemical mechanisms. Blood 2007; 110: 2067–2074.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ye BH, Cattoretti G, Shen Q, Zhang J, Hawe N, de Waard R et al. The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nat Genet 1997; 16: 161–170.

    Article  CAS  PubMed  Google Scholar 

  18. Seyfert VL, Allman D, He Y, Staudt LM . Transcriptional repression by the proto-oncogene BCL-6. Oncogene 1996; 12: 2331–2342.

    CAS  PubMed  Google Scholar 

  19. Shaffer AL, Lin KI, Kuo TC, Yu X, Hurt EM, Rosenwald A et al. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 2002; 17: 51–62.

    Article  CAS  PubMed  Google Scholar 

  20. Turner Jr A, Mack DH, Davis MM . Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells. Cell 1994; 77: 297–306.

    Article  CAS  PubMed  Google Scholar 

  21. Kuo TC, Shaffer AL, Haddad Jr J, Choi YS, Staudt LM, Calame K . Repression of BCL-6 is required for the formation of human memory B cells in vitro. J Exp Med 2007; 204: 819–830.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Malumbres R, Sarosiek KA, Cubedo E, Ruiz JW, Jiang X, Gascoyne RD et al. Differentiation stage-specific expression of microRNAs in B lymphocytes and diffuse large B-cell lymphomas. Blood 2009; 13: 3754–3764.

    Article  Google Scholar 

  23. Zhang J, Jima DD, Jacobs C, Fischer R, Gottwein E, Huang G et al. Patterns of microRNA expression characterize stages of human B-cell differentiation. Blood 2009; 13: 4586–4594.

    Article  Google Scholar 

  24. Tan LP, Wang M, Robertus JL, Schakel RN, Gibcus JH, Diepstra A et al. miRNA profiling of B-cell subsets: specific miRNA profile for germinal center B cells with variation between centroblasts and centrocytes. Lab Invest 2009; 89: 708–716.

    Article  CAS  PubMed  Google Scholar 

  25. Basso K, Sumazin P, Morozov P, Schneider C, Maute RL, Kitagawa Y et al. Identification of the human mature B cell miRNome. Immunity 2009; 30: 744–752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lwin T, Hazlehurst LA, Dessureault S, Lai R, Bai W, Sotomayor E et al. Cell adhesion induces p27Kip1-associated cell-cycle arrest through down-regulation of the SCFSkp2 ubiquitin ligase pathway in mantle-cell and other non-Hodgkin B-cell lymphomas. Blood 2007; 110: 1631–1638.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Li L, Zhang X, Kovacic S, Long AJ, Bourque K, Wood CR et al. Identification of a human follicular dendritic cell molecule that stimulates germinal center B cell growth. J Exp Med 2000; 191: 1077–1084.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Schwarz YX, Yang M, Qin D, Wu J, Jarvis WD, Grant S et al. Follicular dendritic cells protect malignant B cells from apoptosis induced by anti-Fas and antineoplastic agents. J Immunol 1999; 163: 6442–6447.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Rasa Hamilton for editorial assistance. Grant support was provided by the National Cancer Institutes was provided by the (R01CA137123, to JT), Leukemia Research Foundation (to JT) and the Maher Fund (to JT).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to J Tao.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lin, J., Lwin, T., Zhao, JJ. et al. Follicular dendritic cell-induced microRNA-mediated upregulation of PRDM1 and downregulation of BCL-6 in non-Hodgkin's B-cell lymphomas. Leukemia 25, 145–152 (2011). https://doi.org/10.1038/leu.2010.230

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2010.230

Keywords

This article is cited by

Search

Quick links