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Homing mechanisms in the etiopathogenesis of multiple myeloma

par Van Riet, Ivan;Bakkus, Marleen;De Greef, Catherine;Faid, Louiza ;Van Camp, Ben
Référence Stem cells, 13, SUPPL. 2, page (22-27)
Publication Publié, 1995

Article révisé par les pairs

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Résumé :

Although multiple myeloma (MM) is characterized by a monoclonal expansion of plasma cells, it has been assumed that the tumor close also includes more immature B cells. We could demonstrate by DNA sequence analysis of the variable region in immunoglobulin (Ig) heavy chain genes, that myeloma patients have peripheral blood monoclonal B cells that have not switched their Ig isotype but are somatically hypermutated. This finding suggests that myeloma originates from a germinal center B cell 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 them to migrate from the lymph node to the marrow environment. Within the marrow compartment these precursors will receive the appropriate differentiation signals to become mature tumor cells. The growth and survival of these bone marrow (BM) plasma cells is believed to be regulated by a functional interplay with the surrounding marrow stroma involving 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 interaction contributes only partially tn 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 that 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 needed. We established a myeloma cell line (MM 5.1) that grows only on stromal layers cultured from autologous or allogeneic BM and not in the presence of exogenously added IL-6. Recently a stroma- independent variant (MM 5.2) of the cell line has been obtained. This cell line offers a useful model to study the growth regulation of myeloma cells by the marrow stroma, and to unravel the mechanisms that lead to stroma- independent tumor growth as can be observed in refractory and end stage disease patients.