β2-Microglobulin as a multifunctional regulator of myeloma cell growth and survival

β₂-microglobulin (β₂m) is a single non-glycosylated protein that is non-covalently associated, on the cell surface, with the a-chain of the major histocompatibility complex (MHC) class I molecules. Free β₂m is found in body fluids and elevated levels of the protein have been demonstrated in autoimmune and infectious diseases, and in malignancies including multiple myeloma (MM). MM is a B-cell neoplasia characterized by an accumulation of malignant plasma cells in the bone marrow. Myeloma cells produce β2m and the elevated levels of β₂m correlate to poor prognosis of patients. The aim of the present study was to examine whether β;m at elevated levels may affect myeloma cell growth. The results show that β₂m suppressed, in time- and dose-dependent manners, the growth of 3 out of 4 myeloma cell lines tested (ARK-RS, RPMI-8226 and U266). The growth inhibition was mediated via the induction of apoptosis as well as growth arrest in these myeloma cell lines. On the contrary, β₂m enhanced the growth of the other cell line, ARP-1, by reducing the percentage of apoptotic cells in culture and increasing the percentage of cells in S-phase. Furthermore, β;m acts also on freshly isolated primary myeloma cells; a growth inhibition was seen in tumor cells from 3 of 7 patients, while a growth promotion in 2. Tumor cells from the remaining 2 patients did not respond to β₂m treatment. β₂m treatment induced a significant reduction in the density of surface β₂m, while that of the α-chain of the MHC class-I molecules was not affected. Caspase inhibitors abrogated β₂m-induced apoptosis in the cell lines, suggesting that the apoptosis was through the caspase cascade. Taken together, our data demonstrate that β₂m plays an important role in regulating the growth and survival of myeloma cells, and warrant further investigation to delineate the mechanism of βjin-mduced growth regulation in myeloma cells.