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Prepublished online as a Blood First Edition Paper on June 28, 2002; DOI 10.1182/blood-2002-01-0102.
Submitted January 14, 2002
Accepted June 9, 2002
In the presence of bone marrow stromal cells human multiple myeloma cells become independent of the IL-6/gp130/STAT3 pathway
Manik Chatterjee, Dirk Honemann, Suzanne Lentzsch, Kurt Bommert, Christine Sers, Pia Herrmann, Stephan Mathas, Bernd Dorken, and Ralf C Bargou*
Department of Hematology, Oncology and Tumorimmunology, Robert-Rossle Cancer Center at the Max-Delbruck-Center for Molecular Medicine, Charite, Campus Berlin-Buch, Humboldt University of Berlin, Berlin, Berlin, Germany
Institute of Pathology, University Hospital Charite, Berlin, Berlin, Germany
* Corresponding author; email: bargou{at}mdc-berlin.de.
The IL-6/gp130/STAT3 pathway has been reported to play an important role in the pathogenesis of multiple myeloma (MM) and for survival of MM cells. However, most data concerning the role of IL-6 and IL-6-triggered signaling pathways were obtained from experiments performed with MM cell lines and without considering the bone marrow microenvironment. Thus, the precise role of IL-6 and its intracellular signaling pathways for survival of human MM cells is still unclear. Here we show that treatment of human MM cells (IL-6-dependent MM cell line INA-6 and primary MM cells) with the IL-6 receptor-antagonist Sant7 or with an anti-gp130 mAb induced apoptosis if the cells were cultured in the absence of bone marrow stromal cells (BMSCs). In contrast, apoptosis could not be observed if the MM cells were cocultured with BMSCs. The analysis of intracellular pathways revealed that Sant7 and anti-gp130 mAb were effectively inhibiting the phosphorylation of gp130 and STAT3 in the absence and presence of BMSCs, whereas ERK1,2 phosphorylation was only slightly affected. In contrast, treatment with farnesyl transferase inhibitor FPT III induced of apoptosis in MM cells in the absence or presence of BMSCs, and led to a complete inhibition of the Ras/MAPK pathway. These observations indicate that the IL-6/gp130/STAT3 pathway is not essential for survival of human myeloma cells if they are grown in the presence of cells from the bone marrow microenvironment. Furthermore, we provide evidence that farnesyl transferase inhibitors might be useful for the development of novel therapeutic strategies for the treatment of MM.
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