β₂-microglobulin as a negative growth regulator of myeloma cells

High β₂-microglobulin (β₂m) levels in myeloma correlate with poor prognosis. We hypothesized that β₂m may affect myeloma cell growth and survival. In this study, we examined the in vitro effects of β₂m on myeloma cells. Primary myeloma cells freshly isolated from patients and myeloma cell lines were used, cultured in the presence of β₂m, and monitored for growth and survival. β₂m 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 β₂m induced apoptosis and cell cycle arrest. β₂m-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. β₂m-induced growth arrest was associated with downregulation of cyclins A and D2. Surprisingly, anti-β₂m antibodies did not block the effect of β₂m but were synergistic with β₂m, resulting in 90% growth inhibition and 70% apoptosis of myeloma cells. Whereas β₂m treatment resulted in slight upregulation of surface β₂m and major histocompatibility complex class I α-chain expression, treatment of myeloma cells with anti-β₂m antibodies alone or with β₂m resulted in significant downregulation of surface β₂m and class I molecules, suggesting that class I molecules may be involved in signal transduction. Our data demonstrate that β₂m plays an important role in regulating the growth and survival of myeloma cells in vitro and warrants further investigation to delineate the mechanisms of β₂m and anti-β₂m antibody-induced growth regulation of myeloma cells.