Aberrant expression of genes regulating apoptosis/survival seems to be essential in the stepwise development of human multiple myeloma (MM). In this paper we have compared the expression of bcl-2 family pro- and anti-apoptotic genes in MM cell lines, primary MM cells and normal plasma cells. The Bcl-2, Mcl-1, Bcl-xL/S, Bcl-w, Bax, Bak, and Bad were shown to be expressed in both malignant and non-neoplastic, normal plasma cells. Quantitative analysis revealed that the malignant phenotype seemed to correlate with an elevated expression of Mcl-1, a decreased expression of Bax and, to a lesser extent, an increased Bcl-2/Bax expression ratio. The possible influence of interleukin-6 (IL-6) in regulating the expression of the bcl-2-related genes was also examined. Using the IL-6-dependent MM cell lines U-1958 and U-266-1970 it was clearly shown that IL-6 deprivation induced cell cycle arrest in both cell lines, whereas apoptosis was only detected in the U-1958 cells. Furthermore, the anti-apoptotic proteins Bcl-2, Mcl-1 and Bcl-xL were down-regulated, while the expression of the pro-apoptotic Bax protein was increased. To conclude, we suggest that the expression pattern of the Bcl-2 family of proteins separates the malignant phenotype of MM from normal plasma cells, and that the protecting effect of IL-6 may be conducted via an altered balance between these proteins.
Several studies have documented IL‐6‐dependent growth promotion of murine and human neoplastic plasma cells. However, it is well known that human multiple myeloma (MM) cells in vitro show a considerable degree of heterogeneity concerning growth and survival requirements. This heterogeneity, which probably reflects overlapping effects of feeder cells, interleukin 6 (IL‐6) and components of fetal calf serum (FCS) as well as tumour heterogeneity in vivo, has hampered the elucidation of molecular mechanisms underlying the effects of IL‐6. In an attempt to dissociate growth and survival promotion of IL‐6, we have studied two pairs of human MM cell lines, HL407E/HL407L and U‐266‐1970/U‐266‐1984, selected to represent different stages of in vitro tumour progression and dependence of feeder cells and exogenous IL‐6. We demonstrated that exogenous IL‐6, in the presence of FCS, conveyed: (a) a strong growth stimulatory effect with weak or no survival promotion in HL407L and U‐266‐1970 cells; (b) promotion of survival with no effects on growth in HL407E cells; (c) no growth or survival promotion to U‐266‐1984. Moreover, our results suggested that IL‐6 may enhance apoptosis in U‐266‐1970/U‐266‐1984 cells, and that FCS may interfere with IL‐6 in its growth stimulatory effect. The relative dissociation of growth, survival and apoptotic effects of IL‐6 leads to the conclusion that the HL407E/HL407L and U‐266‐1970/U‐266‐1984 pairs of cell lines provide a useful human model system to study molecular mechanisms underlying these separate events.
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