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Prepublished online as a Blood First Edition Paper on September 11, 2003; DOI 10.1182/blood-2003-04-1048.
Submitted April 7, 2003
Accepted August 24, 2003
Interleukin-6-dependent gene expression profiles in multiple myeloma INA-6 cells reveal a Bcl-2-family-independent survival pathway closely associated with Stat3 activation
Katja Brocke-Heidrich, Antje K Kretzschmar, Gabriele Pfeifer, Christian Henze, Dennis Loeffler, Dirk Koczan, Hans-Juergen Thiesen, Renate Burger, Martin Gramatzki, and Friedemann Horn*
Institute of Clinical Immunology and Transfusion Medicine, University of Leipzig, Leipzig, Germany
Department of Immunology, University of Rostock, Faculty of Medicine, University of Rostock, Rostock, Germany
Division of Hematology/Oncology, Department of Medicine III, University of Erlangen-Nuernberg, Erlangen, Germany
* Corresponding author; email: fhorn{at}medizin.uni-leipzig.de.
Interleukin 6 (IL-6) is a growth and survival factor for multiple myeloma cells. As we report here, the IL-6-dependent human myeloma cell line INA-6 responds with a remarkably rapid and complete apoptosis to cytokine withdrawal. Among the anti-apoptotic members of the Bcl-2 family of apoptosis regulators, only Mcl-1 was slightly induced by IL-6. Overexpression studies demonstrated, however, that IL-6 does not exert its survival effect primarily through this pathway. The IL-6 signal transduction pathways required for survival and the target genes controlled by them were analyzed using mutated receptor chimeras. The activation of Stat3 turned out to be obligatory for the survival of INA-6 cells. The same held true for survival and growth of XG-1 myeloma cells. Gene expression profiling of INA-6 cells using oligonucleotide microarrays revealed many novel IL-6 target genes, among them several genes coding for transcriptional regulators involved in B lymphocyte differentiation as well as for growth factors and receptors potentially implicated in autocrine or paracrine growth control. Regulation of most IL-6 target genes required the activation of Stat3 underscoring its central for IL-6 signal transduction. Taken together, our data provide evidence for the existence of an as yet unknown Stat3-dependent survival pathway in myeloma cells.
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