Binding of TACI and APRIL to Syndecan-1 Confer on Them a Major Role in Multiple Myeloma.

B-cell activating factor (BAFF) and A Proliferation-Inducing Ligand (APRIL) are produced by the bone marrow microenvironment of patients with multiple myeloma (MM) and are growth factors of multiple myeloma cells (MMC). BAFF and APRIL share two receptors - TACI and BCMA - and BAFF binds to a third receptor, BAFF-R. We previously reported that TACI expression is a good indicator of a BAFF-binding receptor in human myeloma cell lines (HMCL), unlike BCMA that is expressed on all HMCL. BAFF-R is lacking. More recently, Ingold et al (J Exp Med; 2005) and Hendriks at al (Cell Death Differ; 2005) identified proteoglycans as the APRIL-specific binding partners. Bischof et al (Blood; 2006) demonstrated that TACI binds also heparan sulfate (HS) chains, in particular to syndecan-1, syndecan-2 and syndecan-4. Syndecan-1 is expressed by plasma cells and epithelial cells and is involved in several cellular processes relying on interactions with extra-cellular matrix proteins, growth factors, chemokines and adhesion molecules. We found a very large binding of APRIL (mean fluorescence activity ≥ 500), unlike BAFF, at the surface of all syndecan-1+ HMCL. These syndecan-1+ HMCL also highly bound TACI-Fc molecules, unlike BCMA-Fc or BAFF-R-Fc molecules. This large binding of APRIL or TACI-Fc molecules was abrogated by heparitinase pretreatment of MMC, removing the HS chains or by preincubation of APRIL and TACI-Fc with heparin. These data were extended to patients primary myeloma cells. In agreement with this large binding to MMC, APRIL was 15 to 40 fold more efficient than BAFF to stimulate the growth of HMCL. The APRIL growth factor activity could be inhibited using heparin, unlike that of BAFF. Our data establish that syndecan-1, by concentrating large levels of APRIL and TACI at MMC surface, can promote APRIL/TACI signaling that induces survival and proliferation of MMC. Heparan sulfate chain inhibitors could be helpful to synergize with BAFF/APRIL inhibitors in MM disease.