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Ectopic expression of fibroblast growth factor receptor 3 promotes myeloma cell proliferation and prevents apoptosis.
Plowright, E E; Li, Z; Bergsagel, P L; Chesi, M; Barber, D L; Branch, D R; Hawley, R G; Stewart, A K.
Affiliation
  • Plowright EE; Princess Margaret Hospital, Toronto, Ontario, Canada.
Blood ; 95(3): 992-8, 2000 Feb 01.
Article in En | MEDLINE | ID: mdl-10648414
ABSTRACT
The t(4;14) translocation occurs in 25% of multiple myeloma (MM) and results in both the ectopic expression of fibroblast growth factor receptor 3 (FGFR3) from der4 and immunoglobulin heavy chain-MMSET hybrid messenger RNA transcripts from der14. The subsequent selection of activating mutations of the translocated FGFR3 by MM cells indicates an important role for this signaling pathway in tumor development and progression. To investigate the mechanism by which FGFR3 overexpression promotes MM development, interleukin-6 (IL-6)-dependent murine B9 cells were transduced with retroviruses expressing functional wild-type or constitutively activated mutant FGFR3. Overexpression of mutant FGFR3 resulted in IL-6 independence, decreased apoptosis, and an enhanced proliferative response to IL-6. In the presence of ligand, wild-type FGFR3-expressing cells also exhibited enhanced proliferation and survival in comparison to controls. B9 clones expressing either wild-type FGFR3 at high levels or mutant FGFR3 displayed increased phosphorylation of STAT3 and higher levels of bcl-x(L) expression than did parental B9 cells after cytokine withdrawal. The mechanism of the enhanced cell responsiveness to IL-6 is unknown at this time, but does not appear to be mediated by the mitogen-activated protein kinases SAPK, p38, or ERK. These findings provide a rational explanation for the mechanism by which FGFR3 contributes to both the viability and propagation of the myeloma clone and provide a basis for the development of therapies targeting this pathway.
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Collection: 01-internacional Health context: 6_ODS3_enfermedades_notrasmisibles Database: MEDLINE Main subject: Translocation, Genetic / Chromosomes, Human, Pair 4 / Chromosomes, Human, Pair 14 / Protein-Tyrosine Kinases / Myeloma Proteins / Signal Transduction / Gene Expression Regulation, Neoplastic / Oncogene Proteins, Fusion / Immunoglobulin Heavy Chains / Receptors, Fibroblast Growth Factor Limits: Humans Language: En Journal: Blood Year: 2000 Document type: Article
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Collection: 01-internacional Health context: 6_ODS3_enfermedades_notrasmisibles Database: MEDLINE Main subject: Translocation, Genetic / Chromosomes, Human, Pair 4 / Chromosomes, Human, Pair 14 / Protein-Tyrosine Kinases / Myeloma Proteins / Signal Transduction / Gene Expression Regulation, Neoplastic / Oncogene Proteins, Fusion / Immunoglobulin Heavy Chains / Receptors, Fibroblast Growth Factor Limits: Humans Language: En Journal: Blood Year: 2000 Document type: Article