Abstract
Multiple myeloma (MM) is a clonal B-cell neoplasia characterized by the accumulation of malignant plasma cells within the bone marrow. MM still remains a fatal maligancy. In order to identify new myeloma cell growth factors and new therapeutic targets, we recently compared gene expression profiles of myeloma cells with those of normal plasmablasts and peripheral blood B cells. Interestingly, we found that BAFF and APRIL family members play a important role in MM biology. MM cells express BAFF/APRIL receptors whereas BAFF and APRIL are mainly expressed by the bone marrow microenvironment. We demonstrated BAFF and APRIL are MM cell growth factors. TACI appears to be the functional receptor mediating BAFF/APRIL activity in MM. TACI is overexpressed in patients whose MMC have a gene signature indicative of a dependence on the tumor environment. MMC with low TACI expression overexpress in turn cell cycle genes indicative of a plamablastic signature. Syndecan-1 plays a key role in MM biology concentrating large amount of growth factors at the surface of MM cells. We demonstrated that myeloma cells expressing syndecan-1 can bind high amounts of APRIL and TACI at their cell surface. Our data identify syndecan-1 as coreceptor for APRIL and TACI promoting APRIL/TACI signaling in MMC.<br />Taken together, our findings foster a clinical use of inhibitors interfering with the BAFF/APRIL pathway in MM. This work was followed by a new phase I/II clinical trial using a BAFF/APRIL inhibitor in MM.