β2-microglobulin as a negative growth regulator of myeloma cells

High beta(2) -microglobulin (beta(2) m) levels in myeloma correlate with poor prognosis. We hypothesized that beta(2) m may affect myeloma cell growth and survival. In this study, we examined the in vitro effects of beta(2) m on myeloma cells. Primary myeloma cells freshly isolated from patients and myeloma cell lines were used, cultured in the presence of beta(2) m, and monitored for growth and survival. beta(2) m suppressed the growth of primary tumour cells and myeloma cell lines (ARK-RS, ARP-1, RPMI-8226, U266, ARH-77 and IM-9). High concentrations of beta(2) m induced apoptosis and cell cycle arrest. beta(2) m-induced apoptosis was dependent on activation of a caspase cascade, inhibited by interleukin 6, and did not involve the surface death receptors, as receptor-neutralizing antibodies had no inhibitory effect. beta(2) m-induced growth arrest was associated with downregulation of cyclins A and D2. Surprisingly, anti-beta(2) m antibodies did not block the effect of beta(2) m but were synergistic with beta(2) m, resulting in 90% growth inhibition and 70% apoptosis of myeloma cells. Whereas beta(2) m treatment resulted in slight upregulation of surface beta(2) m and major histocompatibility complex class I alpha-chain expression, treatment of myeloma cells with anti-beta(2) m antibodies alone or with beta(2) m resulted in significant downregulation of surface beta(2) m and class I molecules, suggesting that class I molecules may be involved in signal transduction. Our data demonstrate that beta(2) m plays an important role in regulating the growth and survival of myeloma cells in vitro and warrants further investigation to delineate the mechanisms of beta(2) m and anti-beta(2) m antibody-induced growth regulation of myeloma cells.