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Blood, 1 December 2004, Vol. 104, No. 12, pp. 3712-3721. Prepublished online as a Blood First Edition Paper on August 5, 2004; DOI 10.1182/blood-2004-04-1670. This Article Full Text (PDF) All Versions of this Article: 2004-04-1670v1 104/12/3712    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chatterjee, M. Articles by Bargou, R. C Search for Related Content PubMed PubMed Citation Articles by Chatterjee, M. Articles by Bargou, R. C Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 30, 2004 Accepted July 16, 2004 Combined disruption of both the MEK/ERK and the IL-6R/STAT3 pathways is required to induce apoptosis of multiple myeloma cells in the presence of bone marrow stromal cells Manik Chatterjee*, Thorsten Stuehmer, Pia Herrmann, Kurt Bommert, Bernd Dorken, and Ralf C Bargou Department of Hematology, Oncology, and Tumorimmunology, Robert Roessle Cancer Clinic and HELIOS-Clinics at the Max Delbrueck Center for Molecular Medicine, Charite, Humboldt University, Campus Berlin-Buch, Berlin, Berlin, Germany * Corresponding author; email: manik.chatterjee{at}mdc-berlin.de. The IL-6R/STAT3 pathway contributes to the pathogenesis of multiple myeloma (MM) and protects MM cells from apoptosis. However, MM cells survive IL-6R blockade if they are cocultured with bone marrow stromal cells (BMSCs), suggesting that the BM microenvironment stimulates IL-6-independent pathways that exert a pro-survival effect. The goal of this study was to investigate the underlying mechanism. Detailed pathway analysis revealed that BMSCs stimulate STAT3 via the IL-6R, and MAP kinases via IL-6R-independent mechanisms. Abolition of MEK1,2 activity with PD98059, or ERK1,2 siRNA knockdown, was insufficient to induce apoptosis. However, the combined disruption of the IL-6R/STAT3 and MEK1,2/ERK1,2 pathways led to strong induction of apoptosis even in the presence of BMSCs. This effect was observed with MM cell lines and with primary MM cells, suggesting that the BMSC-induced activation of MEK1,2/ERK1,2 renders MM cells IL-6R/STAT3-independent. Therefore, in the presence of cells from the BM microenvironment combined targeting of different (and independently activated) pathways is required to efficiently induce apoptosis of MM cells. This might have direct implications for the development of future therapeutic strategies for MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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