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  • Title: IL-6-independent expression of Mcl-1 in human multiple myeloma.
    Author: Zhang B, Potyagaylo V, Fenton RG.
    Journal: Oncogene; 2003 Mar 27; 22(12):1848-59. PubMed ID: 12660820.
    Abstract:
    Mcl-1 is a critical antiapoptotic survival factor for human multiple myeloma (MM). We examined the importance of IL-6 for Mcl-1 expression in five MM cell lines and in primary MM cells from 14 patients. While culture of MM.1S cells in IL-6 did induce Mcl-1 expression, four other MM cell lines exhibited high levels of Mcl-1 expression that were unaffected by IL-6. Similarly, Mcl-1 expression in 10 of 14 primary MM isolates was found to be IL-6-independent. An analysis of the mechanisms responsible for IL-6-independent Mcl-1 expression was undertaken. ERK1/2 activity did not influence Mcl-1 expression, distinct from Mcl-1 regulation that occurs during myeloid differentiation from hematopoietic progenitor cells. Inhibition of the PI3K pathway led to growth inhibition of 8226 and ANBL-6 cells without reduction of Mcl-1 levels, and high level Mcl-1 expression was maintained in the absence of activated STAT3. Analysis of the transcriptional activity of 5'-regulatory sequences from the human Mcl-1 gene in MM cells demonstrated high levels of IL-6-independent indicator gene activation as predicted. These data demonstrate that the mechanisms regulating Mcl-1 levels in MM cells are heterogeneous, and are often independent from IL-6 signaling pathways.
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