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Mcl-1 is essential for the survival of plasma cells

Nature Immunology volume 14, pages 290–297 (2013)Cite this article

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A Corrigendum to this article was published on 19 July 2013

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Abstract

The long-term survival of plasma cells is entirely dependent on signals derived from their environment. These extrinsic factors presumably induce and sustain the expression of antiapoptotic proteins of the Bcl-2 family. It is uncertain whether there is specificity among Bcl-2 family members in the survival of plasma cells and whether their expression is linked to specific extrinsic factors. We found here that deletion of the gene encoding the antiapoptotic protein Mcl-1 in plasma cells resulted in rapid depletion of this population in vivo. Furthermore, we found that the receptor BCMA was needed to establish high expression of Mcl-1 in bone marrow but not spleen plasma cells and that establishing this survival pathway preceded the component of plasma cell differentiation that depends on the transcriptional repressor Blimp-1. Our results identify a critical role for Mcl-1 in the maintenance of plasma cells.

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Figure 1: Expression of prosurvival members of the Bcl-2 family in plasma cells.
Figure 2: BCMA regulates Mcl-1 expression in bone marrow plasma cells.
Figure 3: The BCMA pathway is regulated independent of Blimp-1.
Figure 4: Dependence on Mcl-1 in in vitro cultured plasmablasts.
Figure 5: Mcl-1 expression is required for the survival of plasma cells.
Figure 6: Dependence of plasma cells on Mcl-1 is cell intrinsic.

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  • 21 March 2013

    In the version of this article initially published, the number for the National Health and Medical Research Council grant to I.V. is incorrect in the Acknowledgements section. The correct number is 1021374. The error has been corrected in the HTML and PDF versions of the article.

References

  1. Shaffer, A.L. et al. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 17, 51–62 (2002).

    CAS  PubMed  Google Scholar 

  2. Shapiro-Shelef, M. et al. Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity 19, 607–620 (2003).

    CAS  PubMed  Google Scholar 

  3. Kallies, A. et al. Initiation of plasma-cell differentiation is independent of the transcription factor Blimp-1. Immunity 26, 555–566 (2007).

    CAS  PubMed  Google Scholar 

  4. Kallies, A. et al. Plasma cell ontogeny defined by quantitative changes in Blimp-1 expression. J. Exp. Med. 200, 967–977 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Sze, D.M., Toellner, K.M., Garcia de Vinuesa, C., Taylor, D.R. & MacLennan, I.C. Intrinsic constraint on plasmablast growth and extrinsic limits of plasma cell survival. J. Exp. Med. 192, 813–821 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Tarlinton, D. B-cell memory: are subsets necessary? Nat. Rev. Immunol. 6, 785–790 (2006).

    CAS  PubMed  Google Scholar 

  7. Rajewsky, K. Clonal selection and learning in the antibody system. Nature 381, 751–758 (1996).

    CAS  PubMed  Google Scholar 

  8. Kabashima, K. et al. Plasma cell S1P1 expression determines secondary lymphoid organ retention versus bone marrow tropism. J. Exp. Med. 203, 2683–2690 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Tarlinton, D., Radbruch, A., Hiepe, F. & Dorner, T. Plasma cell differentiation and survival. Curr. Opin. Immunol. 20, 162–169 (2008).

    CAS  PubMed  Google Scholar 

  10. Oracki, S.A., Walker, J.A., Hibbs, M.L., Corcoran, L.M. & Tarlinton, D.M. Plasma cell development and survival. Immunol. Rev. 237, 140–159 (2010).

    CAS  PubMed  Google Scholar 

  11. Smith, K.G., Hewitson, T.D., Nossal, G.J. & Tarlinton, D.M. The phenotype and fate of the antibody-forming cells of the splenic foci. Eur. J. Immunol. 26, 444–448 (1996).

    CAS  Google Scholar 

  12. O'Connor, B.P. et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J. Exp. Med. 199, 91–98 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Benson, M.J. et al. Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J. Immunol. 180, 3655–3659 (2008).

    CAS  PubMed  Google Scholar 

  14. Cassese, G. et al. Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals. J. Immunol. 171, 1684–1690 (2003).

    CAS  PubMed  Google Scholar 

  15. Rodriguez Gomez, M. et al. Basophils support the survival of plasma cells in mice. J. Immunol. 185, 7180–7185 (2010).

    PubMed  Google Scholar 

  16. Rozanski, C.H. et al. Sustained antibody responses depend on CD28 function in bone marrow-resident plasma cells. J. Exp. Med. 208, 1435–1446 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Tokoyoda, K., Egawa, T., Sugiyama, T., Choi, B.I. & Nagasawa, T. Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity 20, 707–718 (2004).

    CAS  PubMed  Google Scholar 

  18. Le Gouill, S., Podar, K., Harousseau, J.L. & Anderson, K.C. Mcl-1 regulation and its role in multiple myeloma. Cell Cycle 3, 1259–1262 (2004).

    CAS  PubMed  Google Scholar 

  19. Potter, M. Neoplastic development in plasma cells. Immunol. Rev. 194, 177–195 (2003).

    CAS  PubMed  Google Scholar 

  20. Belnoue, E. et al. APRIL is critical for plasmablast survival in the bone marrow and poorly expressed by early-life bone marrow stromal cells. Blood 111, 2755–2764 (2008).

    CAS  PubMed  Google Scholar 

  21. Moreaux, J. et al. BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood 103, 3148–3157 (2004).

    CAS  PubMed  Google Scholar 

  22. Carrington, E.M. et al. BH3 mimetics antagonizing restricted prosurvival Bcl-2 proteins represent another class of selective immune modulatory drugs. Proc. Natl. Acad. Sci. USA 107, 10967–10971 (2010).

    CAS  PubMed  Google Scholar 

  23. Mérino, D. et al. Bcl-2, Bcl-x(L), and Bcl-w are not equivalent targets of ABT-737 and navitoclax (ABT-263) in lymphoid and leukemic cells. Blood 119, 5807–5816 (2012).

    PubMed  PubMed Central  Google Scholar 

  24. Vikstrom, I. et al. Mcl-1 is essential for germinal center formation and B cell memory. Science 330, 1095–1099 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Tarte, K. et al. The Bcl-2 family member Bfl-1/A1 is strongly repressed in normal and malignant plasma cells but is a potent anti-apoptotic factor for myeloma cells. Br. J. Haematol. 125, 373–382 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Tangye, S.G. Staying alive: regulation of plasma cell survival. Trends Immunol. 32, 595–602 (2011).

    CAS  PubMed  Google Scholar 

  27. Jiang, C., Loo, W.M., Greenley, E.J., Tung, K.S. & Erickson, L.D. B cell maturation antigen deficiency exacerbates lymphoproliferation and autoimmunity in murine lupus. J. Immunol. 186, 6136–6147 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Good, K.L., Avery, D.T. & Tangye, S.G. Resting human memory B cells are intrinsically programmed for enhanced survival and responsiveness to diverse stimuli compared to naive B cells. J. Immunol. 182, 890–901 (2009).

    CAS  PubMed  Google Scholar 

  29. Glaser, S.P. et al. Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia. Genes Dev. 26, 120–125 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Nojima, T. et al. In vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo. Nat. Commun. 2, 465 (2011).

    PubMed  Google Scholar 

  31. Vieira, P. & Rajewsky, K. The half-lives of serum immunoglobulins in adult mice. Eur. J. Immunol. 18, 313–316 (1988).

    CAS  PubMed  Google Scholar 

  32. Amanna, I.J., Carlson, N.E. & Slifka, M.K. Duration of humoral immunity to common viral and vaccine antigens. N. Engl. J. Med. 357, 1903–1915 (2007).

    CAS  PubMed  Google Scholar 

  33. Hammarlund, E. et al. Duration of antiviral immunity after smallpox vaccination. Nat. Med. 9, 1131–1137 (2003).

    CAS  PubMed  Google Scholar 

  34. Crotty, S. et al. Cutting edge: long-term B cell memory in humans after smallpox vaccination. J. Immunol. 171, 4969–4973 (2003).

    CAS  PubMed  Google Scholar 

  35. Radbruch, A. et al. Competence and competition: the challenge of becoming a long-lived plasma cell. Nat. Rev. Immunol. 6, 741–750 (2006).

    CAS  PubMed  Google Scholar 

  36. Chu, V.T. et al. Eosinophils are required for the maintenance of plasma cells in the bone marrow. Nat. Immunol. 12, 151–159 (2011).

    CAS  Google Scholar 

  37. Mohr, E. et al. Dendritic cells and monocyte/macrophages that create the IL-6/APRIL-rich lymph node microenvironments where plasmablasts mature. J. Immunol. 182, 2113–2123 (2009).

    CAS  PubMed  Google Scholar 

  38. Huard, B. et al. APRIL secreted by neutrophils binds to heparan sulfate proteoglycans to create plasma cell niches in human mucosa. J. Clin. Invest. 118, 2887–2895 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Sciammas, R. et al. Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity 25, 225–236 (2006).

    CAS  PubMed  Google Scholar 

  40. Shaffer, A.L. et al. IRF4 addiction in multiple myeloma. Nature 454, 226–231 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Manz, R.A., Hauser, A.E., Hiepe, F. & Radbruch, A. Maintenance of serum antibody levels. Annu. Rev. Immunol. 23, 367–386 (2005).

    CAS  PubMed  Google Scholar 

  42. Novak, A.J. et al. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood 103, 689–694 (2004).

    CAS  PubMed  Google Scholar 

  43. Tangye, S.G., Bryant, V.L., Cuss, A.K. & Good, K.L. BAFF, APRIL and human B cell disorders. Semin. Immunol. 18, 305–317 (2006).

    CAS  PubMed  Google Scholar 

  44. Wuillème-Toumi, S. et al. Mcl-1 is overexpressed in multiple myeloma and associated with relapse and shorter survival. Leukemia 19, 1248–1252 (2005).

    PubMed  Google Scholar 

  45. van Vollenhoven, R.F., Kinnman, N., Vincent, E., Wax, S. & Bathon, J. Atacicept in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase II, randomized, placebo-controlled trial. Arthritis Rheum. 63, 1782–1792 (2011).

    CAS  PubMed  Google Scholar 

  46. Genovese, M.C., Kinnman, N., de La Bourdonnaye, G., Pena Rossi, C. & Tak, P.P. Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: results of a phase II, randomized, placebo-controlled, dose-finding trial. Arthritis Rheum. 63, 1793–1803 (2011).

    CAS  PubMed  Google Scholar 

  47. Kopf, M. et al. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 368, 339–342 (1994).

    CAS  PubMed  Google Scholar 

  48. Borriello, F. et al. B7–1 and B7–2 have overlapping, critical roles in immunoglobulin class switching and germinal center formation. Immunity 6, 303–313 (1997).

    CAS  PubMed  Google Scholar 

  49. Kitamura, D., Roes, J., Kuhn, R. & Rajewsky, K.A. B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature 350, 423–426 (1991).

    CAS  Google Scholar 

  50. Janas, M.L., Hodgkin, P., Hibbs, M. & Tarlinton, D. Genetic evidence for Lyn as a negative regulator of IL-4 signaling. J. Immunol. 163, 4192–4198 (1999).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the facilities of our respective institutes, particularly those responsible for animal husbandry and flow cytometry; and C. Wellard, S. Chevrier, D. Segal, D. Huang, S. Heinzel, J. Marchingo, S. Willis and P. Bouillet for assistance. Supported by the Australia National Health and Medical Research Council (1021374 to I.V.; 356202 to D.M.T. and S.L.N.; 461221 to A.S.; 637326 to S.P.G.; 516786 to K.F.; and the Independent Research Institute Infrastructure Support Scheme), the Multiple Myeloma Research Foundation USA (V.P.), the European Molecular Biology Organization (V.P.), the US National Institutes of Health (AI093722 to L.D.E.) and Victorian State Government Operational Infrastructure Support.

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Author notes

  1. Jennifer Walker

    Present address: Present address: Medical Research Council, Laboratory of Molecular Biology, Cambridge, UK.,

  2. Victor Peperzak and Ingela Vikström: These authors contributed equally to this work.

Authors and Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

    Victor Peperzak, Ingela Vikström, Jennifer Walker, Stefan P Glaser, Andreas Strasser, Stephen L Nutt & David M Tarlinton

  2. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia

    Victor Peperzak, Ingela Vikström, Stefan P Glaser, Andreas Strasser, Stephen L Nutt & David M Tarlinton

  3. Department of Immunology, Monash University, Melbourne, Victoria, Australia

    Melanie LePage, Kirsten Fairfax & Fabienne Mackay

  4. Department of Microbiology, University of Virginia, Charlottesville, Virginia, USA

    Christine M Coquery & Loren D Erickson

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Contributions

V.P., I.V. and D.M.T. designed the research; V.P., I.V., J.W., S.P.G., M.L., C.M.C. and K.F. did experiments and contributed to interpretation and discussion; L.D.E., F.M., A.S. and S.L.N. contributed to the design of experiments, interpretation of results, and drafting the manuscript; V.P. and I.V. analyzed data and prepared figures; and V.P., I.V. and D.M.T. wrote the manuscript.

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Correspondence to David M Tarlinton.

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Peperzak, V., Vikström, I., Walker, J. et al. Mcl-1 is essential for the survival of plasma cells. Nat Immunol 14, 290–297 (2013). https://doi.org/10.1038/ni.2527

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