Résumé
B-cell activating factor (BAFF) and A Proliferation-Inducing Ligand (APRIL) are produced by the BM microenvironment of patients with multiple myeloma (MM) and are growth factors of multiple myeloma cells (MMC). BAFF has three receptors: BAFF-R, TACI and BCMA, and APRIL has 2 receptors: TACI and BCMA. Using real time RT-PCR and FACS analysis, we found that TACI and BCMA are expressed by MMC, unlike BAFF-R. Gene expression profiling (GEP) of purified MMC from newly-diagnosed patients has indicated that primary MMC with high TACI expression (TACI[suphigh] MMC) have a mature plasma cell gene signature linked to a dependence on the bone marrow environment. In contrast, primary MMC with a low TACI expression (TACI[suplow] MMC) have a gene signature of proliferating plasmablasts. TACI expression was either undetectable (11 HMCLs) or present (7 HMCLs) on a panel of 18 HMCLs, whereas BCMA expression was detected in all HMCLs with sensitive real-time RT-PCR and FACS analysis. GEP of the 18 HMCLs were determined with Affymetrix U133 DNA microarrays that interrogate 33000 genes or ESTs. 109 out of the 33000 genes/ESTs were differentially expressed between TACI[sup+] and TACI[sup-] HMCLs (ratio ≤ 0.5 and ≥ 2, P ≤ 0.05). TACI[sup+] HMCLs have a gene signature indicative of a BM environment dependence close to that of normal bone marrow plasma cells, including genes involved in intercellular communication and signal transduction genes. TACI[sup+] HMCLs with a BM environment dependence signature include the RPMI8226 and LP1 HMCLs that produce BAFF or APRIL as autocrine growth factors, a property of the bone marrow environment in patients with intramedullary MM. The microenvironment dependence signature was also found in 5 HMCLs (XG-2, XG-12, XG-13, XG-19 and XG-20) whose growth requires addition of exogenous IL-6 or BAFF/APRIL in vitro. These data indicate that a high TACI expression and the associated microenvironment dependence gene signature found in primary MMC is kept in HMCLs that have been maintained in culture for 10–30 years, and whose growth does not need anymore interaction with BM environment. One hypothesis is that this gene signature may be a characteristic of the MMC clone at the occurrence of the disease. The MM stem cell could be immortalized at different stages of normal plasma cell differentiation. Transformation at the plasmablastic stage would give rise to a MMC clone with a plasmablastic gene signature. Transformation at a later plasma cell differentiation stage would give rise to a MMC clone with a gene signature of mature BM plasma cells.