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.
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 antiapoptotic members of the B-cell lymphoma-2 (Bcl-2) family of apoptosis regulators, only myeloid cell factor-1 (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 by using mutated receptor chimeras. The activation of signal transducer and activator of transcription 3 (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 by 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 role 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.
Brocke-Heidrich
Katja
K
Institute of Clinical Immunology and Transfusion Medicine, University Hospital Leipzig, Johannisallee 30, 04103 Leipzig, Germany. fhorn@medizin.uni-leipzig.de
Kretzschmar
Antje K
AK
Pfeifer
Gabriele
G
Henze
Christian
C
Löffler
Dennis
D
Koczan
Dirk
D
Thiesen
Hans-Jürgen
HJ
Burger
Renate
R
Gramatzki
Martin
M
Horn
Friedemann
F
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050822:Cytokine Receptor gp130; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020869:Gene Expression Profiling; D019254:Genes, bcl-2; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D017467:Receptors, Erythropoietin / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*
D015703:Antigens, CD; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C494199:IL6ST protein, human; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D050822:Cytokine Receptor gp130