HOMING MECHANISMS IN THE ETIOPATHOGENESIS OF MULTIPLE-MYELOMA

Although multiple myeloma (MM) is characterized by a monoclonal expans ion of plasma cells, it has been assumed that the tumor clone also inc ludes more immature B cells, We could demonstrate by DNA sequence anal ysis of the variable region in immonuglobulin (Ig) heavy chain genes, that myeloma patients have peripheral blood monoclonal B cells that ha ve not switched their Ig isotype but are somatically hypermutated, Thi s finding suggests that myeloma originates from a germinal center B ce ll of the lymph node, most probably a memory B cell or B lymphoblast. The identification of these cells in the peripheral blood circulation implies that they must be equipped with homing receptors that allow th em to migrate from the lymph node to the marrow environment, Within th e marrow compartment these precursors will receive the appropriate dif ferentiation signals to become mature tumor cells, The growth and surv ival of these bone marrow (BM) plasma cells is believed to be regulate d by a functional interplay with the surrounding marrow stroma involvi ng different adhesive mechanisms and the action of several cytokines, We found that myeloma plasma cells express several adhesion molecules (ICAM-1, N-CAM, CD44, VLA-4), Myeloma cell lines can bind to purified fibronectin (FN) using mostly the VLA-4 receptor, However this interac tion contributes only partially to binding with intact stromal layers, Although the main growth stimulating factor of myeloma cells has been identified as interleukin 6 (IL-6), in vitro experiments revealed tha t this cytokine can only induce a short-term proliferation of myeloma cells and does not seem to support the self-renewal of the clonogenic cell, Therefore (an) additional stroma-associated factor(s) might be n eeded, We established a myeloma cell line (MM 5.1) that grows only on stromal layers cultured from autologous or allogeneic BM and not in th e presence of exogenously added IL-6, Recently a stroma-independent va riant (MM 5.2) of the cell line has been obtained, This cell line offe rs a useful model to study the growth regulation of myeloma cells by t he marrow stroma, and to unravel the mechanisms that lead to stroma-in dependent tumor growth as can be observed in refractory and end stage disease patients.