A Proliferation-Inducing Ligand (APRIL): The Development of Antagonistic Agents as Potential Therapeutics and Deciphering the Role of Heparan Sulphate Proteoglycans (HSPGs) in APRIL Signalling

  • Fiona Kimberley
  • Marco Guadagnoli
  • Hans van Eenennaam
  • Jan Paul Medema
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 691)


APRIL (a proliferation-inducing ligand or TALL-2 and TRDL-1) is a member of the tumour necrosis factor (TNF) superfamily and binds two TNF receptors: TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) and BCMA (B-cell maturation antigen). APRIL is important for the maintenance of humoral immune responses, although was originally discovered due to its role in promoting tumourigenic responses. APRIL has since been shown to be involved in several autoimmune diseases and is also implicated as an important pro-survival factor in several B-cell malignancies. To target APRIL specifically for therapeutic purposes, we are developing novel APRIL antagonistic monoclonal antibodies. Here we describe the characterisation of these antibodies and the future direction of our studies. In addition we have performed experiments to further decipher the role of heparan sulphate proteoglycan (HSPG) interactions in APRIL signalling. We report that the HSPG interaction provides a platform for APRIL cross-linking and oligomerisation to signal effectively via BCMA and TACI, but does not appear to mediate direct signalling. The role of APRIL in solid tumours lacking the known APRIL receptors is also addressed.


Multiple Myeloma Tumour Necrosis Factor Receptor Heparan Sulphate Proteoglycan Transmembrane Activator Multiple Myeloma Cell Line 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This research was performed within the framework of project T3.112 of the Dutch Top Institute Pharma and was supported by the Dutch Cancer Society grant 2007-3750


  1. 1.
    Belnoue E, Pihlgren M et al (2008) APRIL is critical for plasmablast survival in the bone marrow and poorly expressed by early life bone marrow stromal cells. Blood 111(5):2755–2764. Epub 2008 Jan 7Google Scholar
  2. 2.
    Benson MJ, Dillon SR et al (2008) Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J Immunol 180(6):3655–3659PubMedGoogle Scholar
  3. 3.
    Bossen C, Cachero TG et al (2008) TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts. Blood 111(3):1004–1012. Epub 2007 Oct 17Google Scholar
  4. 4.
    Castigli E, Scott S et al (2004) Impaired IgA class switching in APRIL-deficient mice. Proc Natl Acad Sci U S A 101(11):3903–3908CrossRefPubMedGoogle Scholar
  5. 5.
    Dillon SR, Gross JA et al (2006) An APRIL to remember: novel TNF ligands as therapeutic targets. Nat Rev Drug Discov 5(3):235–246CrossRefPubMedGoogle Scholar
  6. 6.
    Ding W, Ju S et al (2009) Reduced APRIL expression induces cellular senescence via a HSPG-dependent pathway. Pathol Oncol Res 15(4):693–701. Epub 2009 May 26Google Scholar
  7. 7.
    Ding W, Wang J et al (2009) APRIL knockdown suppresses migration and invasion of human colon carcinoma cells. Clin Biochem 42(16–17):1694–1698. Epub 2009 Jun 30Google Scholar
  8. 8.
    Gatto B (2008) Atacicept, a homodimeric fusion protein for the potential treatment of diseases triggered by plasma cells. Curr Opin Investig Drugs 9(11):1216–1227PubMedGoogle Scholar
  9. 9.
    Hahne M, Kataoka T et al (1998) APRIL, a new ligand of the tumor necrosis factor family, stimulates tumor cell growth. J Exp Med 188(6):1185–1190CrossRefPubMedGoogle Scholar
  10. 10.
    Hatzoglou A, Roussel J et al (2000) TNF receptor family member BCMA (B cell maturation) associates with TNF receptor-associated factor (TRAF) 1, TRAF2, and TRAF3 and activates NF-kappa B, elk-1, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase. J Immunol 165(3):1322–1330PubMedGoogle Scholar
  11. 11.
    Hendriks J, Planelles L et al (2005) Heparan sulfate proteoglycan binding promotes APRIL-induced tumor cell proliferation. Cell Death Differ 12(6):637–648CrossRefPubMedGoogle Scholar
  12. 12.
    Huard B, McKee T et al (2008) APRIL secreted by neutrophils binds to heparan sulfate proteoglycans to create plasma cell niches in human mucosa. J Clin Invest 118(8):2887–2895. Erratum in: J Clin Invest. 2010 Apr;120(4):1362Google Scholar
  13. 13.
    Ingold K, Zumsteg A et al (2005) Identification of proteoglycans as the APRIL-specific binding partners. J Exp Med 201(9):1375–1383CrossRefPubMedGoogle Scholar
  14. 14.
    Kimberley FC, Hahne M et al (2009) APRIL hath put a spring of youth in everything. Relevance of APRIL for survival. J Cell Physiol 218(1):1–8CrossRefPubMedGoogle Scholar
  15. 15.
    Kimberley FC, Medema JP et al (2009) APRIL in B-cell Malignancies and Autoimmunity. Results Prob Cell Differ 49:161–182. ReviewGoogle Scholar
  16. 16.
    Kimberley FC, van Bostelen L et al (2009) The proteoglycan (heparan sulfate proteoglycan) binding domain of APRIL serves as a platform for ligand multimerization and cross-linking. Faseb J 23(5):1584–1595CrossRefPubMedGoogle Scholar
  17. 17.
    Liu Y, Xu L, Opalka N, Kappler J, Shu HB, Zhang G (2002) Crystal structure of sTALL-1 reveals a virus-like assembly of TNF family ligands. Cell 108(3):383–394CrossRefPubMedGoogle Scholar
  18. 18.
    Mackay F, Silveira PA et al (2007) B cells and the BAFF/APRIL axis: fast-forward on autoimmunity and signaling. Curr Opin Immunol 19(3):327–336CrossRefPubMedGoogle Scholar
  19. 19.
    Massacand JC, Kaiser P et al (2008) Intestinal bacteria condition dendritic cells to promote IgA production. PLoS One 3(7):e2588CrossRefPubMedGoogle Scholar
  20. 20.
    Moreaux J, Cremer FW et al (2005) The level of TACI gene expression in myeloma cells is associated with a signature of microenvironment dependence versus a plasmablastic signature. Blood 106(3):1021–1030CrossRefPubMedGoogle Scholar
  21. 21.
    Moreaux J, Legouffe E et al (2004) BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood 103(8):3148–3157CrossRefPubMedGoogle Scholar
  22. 22.
    Moreaux J, Sprynski AC, Dillon SR, Mahtouk K, Jourdan M, Ythier A, Moine P, Robert N, Jourdan E, Rossi JF, Klein B (2009) APRIL and TACI interact with syndecan-1 on the surface of multiple myeloma cells to form an essential survival loop. Eur J Haematol 83(2):119–129. Epub 2009 May 30Google Scholar
  23. 23.
    Planelles L, Carvalho-Pinto CE et al (2004) APRIL promotes B-1 cell-associated neoplasm. Cancer Cell 6(4):399–408CrossRefPubMedGoogle Scholar
  24. 24.
    Planelles L, Castillo-Gutierrez S et al (2007) APRIL but not BLyS serum levels are increased in chronic lymphocytic leukemia: prognostic relevance of APRIL for survival. Haematologica 92(9):1284–1285CrossRefPubMedGoogle Scholar
  25. 25.
    Pradet-Balade B, Medema JP et al (2002) An endogenous hybrid mRNA encodes TWE-PRIL, a functional cell surface TWEAK-APRIL fusion protein. Embo J 21(21):5711–5720CrossRefPubMedGoogle Scholar
  26. 26.
    Rennert P, Schneider P et al (2000) A soluble form of B cell maturation antigen, a receptor for the tumor necrosis factor family member APRIL, inhibits tumor cell growth. J Exp Med 192(11):1677–1684CrossRefPubMedGoogle Scholar
  27. 27.
    Sakurai D, Hase H et al (2007) TACI regulates IgA production by APRIL in collaboration with HSPG. Blood 109(7):2961–2967PubMedGoogle Scholar
  28. 28.
    Schneider P, Takatsuka H et al (2001) Maturation of marginal zone and follicular B cells requires B cell activating factor of the tumor necrosis factor family and is independent of B cell maturation antigen. J Exp Med 194(11):1691–1697CrossRefPubMedGoogle Scholar
  29. 29.
    Swee LK, Ingold-Salamin K et al (2009) Biological activity of ectodysplasin a is conditioned by its collagen and heparan sulfate proteoglycan-binding domains. J Biol Chem 284(40):27567–27576. Epub 2009 Aug 5Google Scholar
  30. 30.
    Tezuka H, Abe Y et al (2007) Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells. Nature 448(7156):929–933CrossRefPubMedGoogle Scholar
  31. 31.
    Xia XZ, Treanor J et al (2000) TACI is a TRAF-interacting receptor for TALL-1, a tumor necrosis factor family member involved in B cell regulation. J Exp Med 192(1):137–143CrossRefPubMedGoogle Scholar
  32. 32.
    Yaccoby S, Pennisi A et al (2008) Atacicept (TACI-Ig) inhibits growth of TACI(high) primary myeloma cells in SCID-hu mice and in coculture with osteoclasts. Leukemia 22:406–413CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Fiona Kimberley
    • 1
  • Marco Guadagnoli
    • 1
  • Hans van Eenennaam
    • 2
  • Jan Paul Medema
    • 1
  1. 1.LEXOR (Laboratory of Experimental Oncology and Radiobiology)Center for Experimental Molecular Medicine, Academic Medical Center (AMC), University of AmsterdamAmsterdamThe Netherlands
  2. 2.Department of Immune TherapeuticsMerck Research LaboratoriesOssThe Netherlands

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