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IL-6-independent expression of Mcl-1 in human multiple myeloma

Oncogene volume 22, pages 1848–1859 (2003)Cite this article

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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Acknowledgements

We thank Dr Steven W Edwards (University of Liverpool, UK) for kindly providing luciferase expression vectors containing 3.9 kb, 294 bp, or 140 bp of the human Mcl-1 gene 5′-regulatory sequences. Dr Steven T Rosen (Northwestern University, Chicago, IL, USA) kindly provided the MM.1S cell line.

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  1. University of Maryland Greenebaum Cancer Center, Baltimore, 21201, MD, USA

    Bin Zhang, Valeria Potyagaylo & Robert G Fenton

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  1. Bin Zhang
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  2. Valeria Potyagaylo
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Correspondence to Robert G Fenton.

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Zhang, B., Potyagaylo, V. & Fenton, R. IL-6-independent expression of Mcl-1 in human multiple myeloma. Oncogene 22, 1848–1859 (2003). https://doi.org/10.1038/sj.onc.1206358

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