Regulation of apoptosis in human multiple myeloma

Abstract: Multiple myeloma (MM) is a clonal expansion of malignant plasmablasts-plasma cells in the bone marrow. MM is slowly proliferating and an increased resistance to apoptosis may be crucial for the tumor progression. By the use of MM cell lines and primary cells the role of some growth factors, and genes regulating survival or apoptosis in human MM cell lines and primary cells, was investigated. The in vitro requirements for growth and survival of MM cells are heterogenous. This has hampered studies of molecular mechanisms underlying the effects of interleukin-6 (IL-6). The results of this thesis showthat IL-6, in the presence of serum, can convey survival dissociated from the effects of IL-6 on proliferation in two pairs of MM cell lines, U-266-1970/U-266-1984 and HL407E/HL407L. In the absence of serum IL-6 may also augment apoptosis. The findings therefore provide a useful human model system of IL-6 dependent and independent cell lines to study the molecular mechanisms underlying IL-6 effects in MM.The thesis also report on the expression of seven Bcl-2 related proteins; Bcl-2, Mcl-1, Bcl-x, Bcl-w, Bax, Bak, and Bad in MM cell lines and normal plasma cells. Elevated expression levels of Bcl-2 and Mel-1, as well as decreased levels of Bax expression were demonstrated in MM cells, and may therefore be associated with the malignant phenotype. Downregulation of the expression of Bcl-2, Mcl-1, and Bcl-x, and an upregulated Bax expression were recorded as a result of IL-6 deprivation in two IL-6 dependent-MM cell lines.A poor response to Fas and dexamethasone induced apoptosis is evident in some MM cell lines and primary cells. We here report that sensitivity to Fas mediated apoptosis can be augmented by IFN-γ or IFN-α in the U-266-1970, U-266-1984, and U-1958 cell lines. The mechanism by which IFNs regulate the sensitivity to apoptosis is unknown. IFNs increased the Fas antigen expression in one of three cell lines, but did not alter the expression of Bcl-2, or Bax, and was shown to be independent of growth inhibition.We also present results showing that IGF-IR signaling can mediate resistance to anti-Fas and dexamethasone induced apoptosis in two IGF-I responsive MM cell lines, LP-1 and Karpas 707. The results show that IGF-IR signaling may be a potent inhibitor of apoptosis, but does not counteract the growth inhibitory effect of dexamethasone in MM cell lines. Taken together this thesis provides important insights in the regulation of cell survival in MM cells by IL-6 and IGF-I, and suggests possible regulators of sensitivity to induced apoptosis in MM.

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