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.

  • Letter to the Editor
  • Published:

BAFF and APRIL as osteoclast-derived survival factors for myeloma cells: a rationale for TACI-Fc treatment in patients with multiple myeloma

Leukemia volume 20, pages 1313–1315 (2006)Cite this article

The fact that multiple myeloma (MM) almost exclusively grows and expands in the bone marrow and develops devastating bone destruction suggests the importance of the bone marrow microenvironment in growth and survival of MM cells. We and others have previously demonstrated that the growth and survival of MM cells are potently enhanced by a cell-to-cell interaction between MM cells and osteoclasts, and that a vicious cycle is formed between MM cells and osteoclasts for their growth and bone destruction.1, 2 Importantly, osteoclasts also protect MM cells from apoptosis induced by doxorubicin, suggesting that increased osteoclast number and/or activity contribute to aggressiveness or drug resistance of MM cells. Interleukin (IL)-6 is regarded as a major growth-promoting and antiapoptotic factor for MM cells, and is mainly produced by bone marrow microenvironment in MM. The effects of osteoclasts in enhancing MM cell growth and survival are, however, only partially inhibited by abrogating IL-6 actions, despite an increased production of IL-6 by osteoclasts via the interaction with MM cells.1 These results suggest that osteoclast-derived factor(s) other than IL-6 is involved in osteoclast-mediated enhancement of growth and survival of MM cells.

B-cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL), members of tumor necrosis factor (TNF) family, have been implicated as growth and survival factors for cytokine-stimulated MM cells.3, 4 B-cell-activating factor binds to three TNF receptor family members, B-cell maturation antigen (BCMA), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), and BAFF receptor (BAFF-R), whereas APRIL binds to BCMA, TACI and heparan sulfate proteoglycans such as syndecan-1.5 Multiple myeloma cells in primary culture constitutively express BCMA as well as syndecan-1,3, 4 whereas TACI is preferentially expressed by MM cells dependent on bone marrow microenvironment.6 B-cell-activating factor receptor is expressed only occasionally.3, 4 Addition of BAFF and APRIL activates nuclear factor-kappaB (NF-κB), phosphatidylinositol-3 kinase (PI3K) to Akt and mitogen-activated protein kinase (MAPK) pathways and induces a strong upregulation of Mcl-1 and Bcl-2 antiapoptotic proteins in MM cells.4 The serum levels of BAFF and APRIL are increased about fivefold in patients with MM as compared with healthy donors.4 Analyses of BAFF and APRIL expression in cells from bone marrow microenvironment of MM patients by quantitative PCR or enzyme-linked immunosorbent assay revealed that CD14+ cells and osteoclasts abundantly express both factors, whereas normal B cells, primary MM cells and bone marrow stromal cells produce much lower levels.6 These results suggest that osteoclasts are among the predominant cell sources of BAFF and APRIL in the MM bone marrow microenvironment. Based upon these observations, a phase I/II clinical study of TACI-Fc fusion protein, a potent inhibitor for both BAFF and APRIL to abrogate BAFF and APRIL actions, in patients with refractory or relapsed MM, is ongoing.7 However, the role of these osteoclast-derived factors in osteoclast-mediated MM cell growth and survival is still unclear.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1

References

  1. Abe M, Hiura K, Wilde J, Shioyasono A, Moriyama K, Hashimoto T et al. Osteoclasts enhance myeloma cell growth and survival via cell–cell contact: a vicious cycle between bone destruction and myeloma expansion. Blood 2004; 104: 2484–2491.

    Article  CAS  Google Scholar 

  2. Yaccoby S, Wezeman MJ, Henderson A, Cottler-Fox M, Yi Q, Barlogie B et al. Cancer and the microenvironment: myeloma–osteoclast interactions as a model. Cancer Res 2004; 64: 2016–2023.

    Article  CAS  Google Scholar 

  3. Novak AJ, Darce JR, Arendt BK, Harder B, Henderson K, Kindsvogel W et al. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood 2004; 103: 689–694.

    Article  CAS  Google Scholar 

  4. Moreaux J, Legouffe E, Jourdan E, Quittet P, Reme T, Lugagne C et al. BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood 2004; 103: 3148–3157.

    Article  CAS  Google Scholar 

  5. Ingold K, Zumsteg A, Tardivel A, Huard B, Steiner QG, Cachero TG et al. Identification of proteoglycans as the APRIL-specific binding partners. J Exp Med 2005; 201: 1375–1383.

    Article  CAS  Google Scholar 

  6. Moreaux J, Cremer FW, Reme T, Raab M, Mahtouk K, Kaukel P et al. The level of TACI gene expression in myeloma cells is associated with a signature of microenvironment dependence versus a plasmablastic signature. Blood 2005; 106: 1021–1030.

    Article  CAS  Google Scholar 

  7. Rossi JF, Borghini-Fuhrer I, Moreaux J, Requirand G, Bouseida S, Picard M et al. 770-II, a phase I/II study of TACI-Ig to neutralize APRIL and BLyS in patients with refractory or relapsed multiple myeloma or active previously-treated Waldenstrom's macroglobulinemia. Blood 2005; 106 (Suppl 1): 712a.

    Google Scholar 

Download references

Acknowledgements

This work was supported in part by the Grant-in-Aid for Scientific Research on Priority Areas (B) to TM, and the Grants-in-Aid for Scientific Research (B) to TM, and (C) to MA from the Ministry of Education, Culture, Science and Sports of Japan and the Grants-in-Aid for Cancer Research (17-17) from the Ministry of Health, Labor and Welfare of Japan. Author's Disclosures of Potential Conflicts of Interest: The authors indicated no potential conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, Tokushima, Japan

    M Abe, S Kido, A Nakano, A Oda, H Amou & T Matsumoto

  2. Department of Orthodontics, University of Tokushima School of Dentistry, Tokushima, Japan

    M Hiasa

Authors
  1. M Abe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Kido
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Hiasa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Nakano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Oda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. H Amou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Abe, M., Kido, S., Hiasa, M. et al. BAFF and APRIL as osteoclast-derived survival factors for myeloma cells: a rationale for TACI-Fc treatment in patients with multiple myeloma. Leukemia 20, 1313–1315 (2006). https://doi.org/10.1038/sj.leu.2404228

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404228

This article is cited by

Search

Advanced search

Quick links