Significance of macrophage inflammatory protein-1 alpha (MIP-1α) in multiple myeloma

Abstract

Macrophage inflammatory protein-1 alpha (MIP-1α) is a member of the CC chemokine family and is primarily associated with cell adhesion and migration. It is produced by myeloma (MM) cells and directly stimulates osteoclast formation and differentiation in a dose dependent way. MIP-1α protein levels were elevated in the bone marrow plasma of MM patients and correlated with disease stage and activity. MIP-1α was also elevated in the serum of myeloma patients with severe bone disease and correlated positively with bone resorption markers providing evidence for a causal role of MIP-1α in the development of lytic bone lesions in MM. MIP-1α has also been found to stimulate proliferation, migration and survival of plasma cells. Mice, which were inoculated with myeloma cells and treated with a monoclonal rat anti-mouse MIP-1α antibody, showed a reduction of both paraprotein and lytic lesions. In addition, MIP-1α enhanced adhesive interactions between myeloma and marrow stromal cells, increasing the expression of RANKL and IL-6, which further increased bone destruction and tumor burden. Myeloma patients with high MIP-1α serum levels have poor prognosis. The positive correlation between MIP-1α and β2-microglobulin that has been observed in MM patients at diagnosis further supports the notion that MIP-1α is not only a chemokine with osteoclast activity function but is also implicated in myeloma growth and survival. Therefore, MIP-1α pathway may serve as a target for the development of novel anti-myeloma therapies.