Homing mechanisms in the biology of multiple myeloma.

Throughout the last decades, new developments in cellular and molecular immunology have led to a better insight in the biological nature of MM. Ever since, MM has also been regarded as a tool for studying basic concepts of the terminal B cell differentiation. The first aim of our research work, was to clarify the intraclonal maturation of the tumor clone by examining the existence of myeloma precursor cells at the genetic level. We found that myeloma patients have monoclonal B cells in the peripheral blood and bone marrow which are more immature as the malignant plasma cells and have passed through the stage of antigen selection in the germinal centre. The detection of these myeloma-related cells in the circulation implicates that these cells must be equipped with the appropriate surface receptors that allow transendothelial migration. Once entered in the marrow compartment, the myeloma cells anchor to the stromal environment where they receive the appropriate signals to proliferate and differentiate. We demonstrated that the bone marrow plasma cells express several adhesion molecules that have the potential to interact with stromal elements. We found that myeloma cell lines can bind to fibronectin (FN) and moreover are able to produce FN themselves. Functional assays revealed that FN plays only a minor role in myeloma cell binding to intact stroma, indicating the existence of other and/or multiple adhesive mechanisms. The growth of myeloma cells in the marrow compartment is not only dependent on adhesive interactions but also included the action of locally produced soluble factors. Although IL-6 has been identified as the major growth factor of myeloma cells, maintenance of tumor growth in vivo depends on one or more additional stroma-derived factors. We could establish a unique human myeloma cell line (MM5.1) that grows only in the presence of cultured human bone marrow stroma or stromal conditioned medium and not when cultured with exogeneous IL-6 alone. More recently a stroma-independent variant (MM5.2) of this line was obtained. We found that the growth of MM5.1 cells is mediated by signaling via the gp-130 transducer chain and involves IL-6 acting with a cofactor. The nature of this stromal cofactor is currently under investigation. Both variants of the cell line are also used to study differential expression of genes that are involved in clonal progression towards stroma-independency and extramedullary growth, as can be observed in patients with end stage disease.