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Objectives: Fibroblast growth factor receptor 3 ( FGFR3) is a proto-oncogene that is often dysregulated together with multiple myeloma SET-domain (MMSET) by the immunoglobulin heavy chain (IGH) gene in t(4;14)pos multiple myeloma (MM) cells, and which is usually not expressed in MM cells without this translocation. Whether FGFR3 may play a role in MM cells without t(4;14) and the IGH-MMSET fusion protein is unclear and is the focus of this report. Methods: FGFR3 expression was explored in cell lines with and without t(4;14) by fluorescence in situ hybridization (FISH), RT-PCR and Western Blot. FGFR3 inhibitors SU5402 and PD173074 were used to explore the role of FGFR3 in these cells. Results: We discovered an amplification of the FGFR3 locus in INA-6, a human MM cell line. We also demonstrated expression of FGFR3 mRNA and protein in the cells, probably caused by the extra copy of the gene. INA-6 cells did not have t(4;14) and neither was there any involvement of the other IG loci in translocations with the FGFR3 gene. The FGFR3 inhibitors decreased the proliferation of INA-6. Conclusion: The decreased viability and proliferation in INA-6, following inhibition with FGFR3 inhibitors, indicates that FGFR3 may play a role also in cells without t(4;14) – and hence without high expression of MMSET, the ubiquitous oncoprotein in MM cells with t(4;14). This gives further credibility to the notion that FGFR3 expression is not just an epiphenomenon in t(4;14) MM, but an important part of the malignant phenotype. [ABSTRACT FROM AUTHOR]

Objectives: Hepatocyte growth factor (HGF) is a constituent of the myeloma microenvironment and is elevated in sera from myeloma patients compared to healthy individuals. Increased levels of serum HGF predict a poor prognosis. It has previously been shown by us and others HGF can act as a growth factor to myeloma cells in vitro although these effects have been moderate. We therefore wanted to investigate if HGF could influence the effects of interleukin (IL)-6. Methods: Myeloma cell lines and primary samples were tested for the combined effects of IL-6 and HGF in inducing DNA synthesis and migration. Expression levels of c-Met protein were analysed by Western blotting and flow cytometry. Signaling pathways were examined by Western blotting using phosphospecific antibodies and a Ras-GTP pull down assay. Results: HGF potentiated IL-6-induced growth in human myeloma cell lines and in purified primary myeloma cells. There was also cooperation between HGF and IL-6 in induction of migration. There seemed to be two explanations for this synergy. IL-6-treatment increased the expression of c-Met making cells HGF responsive, and IL-6 was dependent on c-Met signaling in activating both Ras and p44/42 MAPK by a mechanism involving the tyrosine phosphatase Shp2. Conclusions: The results indicate that besides from being a myeloma growth factor alone, HGF can also potentiate the effects of IL-6 in myeloma proliferation and migration. Thus, c-Met signaling could be a target for therapy of multiple myeloma. [ABSTRACT FROM AUTHOR]