Summary. High b 2 -microglobulin (b 2 m) levels in myeloma correlate with poor prognosis. We hypothesized that b 2 m may affect myeloma cell growth and survival. In this study, we examined the in vitro effects of b 2 m on myeloma cells. Primary myeloma cells freshly isolated from patients and myeloma cell lines were used, cultured in the presence of b 2 m, and monitored for growth and survival. b 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 b 2 m induced apoptosis and cell cycle arrest. b 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 receptorneutralizing antibodies had no inhibitory effect. Multiple myeloma (MM) is a B-cell neoplasm characterized by the accumulation of malignant plasma cells in the bone marrow; it accounts for 1% of all cancers and 10% of all haematological malignancies. MM is still an incurable disease. With conventional chemotherapy, complete remission rates have not exceeded 5% and median survival has not been extended beyond 3 years (Alexanian & Dimopoulos, 1994;Barlogie, 1995). Melphalan-based high-dose therapy with autologous haematopoietic stem cell support has increased complete remission rates by up to 50% and extended survival beyond 6 years (Barlogie et al, 1999), depending on prognostic factors (Bataille et al, 1984;Cuzick et al, 1985;Hallek et al, 1998;Barlogie et al, 1999). The level of b 2 -microglobulin (b 2 m) is one of the most important independent predictors of survival (Bataille et al, 1984;Cuzick et al, 1985), attesting to an important yet unidentified role of b 2 m in MM. In vitro studies show that primary myeloma cells (Bataille et al, 1988) and myeloma cell lines (Brenning et al, 1986) produce high levels of b 2 m. Thus, it is presumed that myeloma cells contribute to the high levels of serum b 2 m, which therefore has been considered an indicator of tumour burden.b 2 m is a 11AE6 kDa non-glycosylated polypeptide composed of 100 amino acids. It is one of the major histocompatibility complex (MHC) class I molecules on the cell surface of all nucleated cells. Its best-characterized function is to interact with and stabilize the tertiary structure of the MHC class I a-chain (Bjorkman & Parham, 1990). Because it is non-covalently associated with the a-chain and has no direct attachment to the cell membrane, b 2 m on the cell surface can exchange with free b 2 m present in serumcontaining medium (Hyafil & Strominger, 1979;Parker & Strominger, 1985). Free b 2 m is found in body fluids under physiological conditions as a result of shedding from cell surfaces or intracellular release. b 2 m is almost exclusively catabolized within the kidney; at least 95% and possibly 100% of circulating b 2 m is eliminated via glomerular filtration (Karlsson et al, 1980). In normal individuals, the serum concentration of b 2 m is usually < 2 mg/l and the urinary excretion < 400 lg/24 h (Sch...
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