title: Overexpression of the myeloma-associated oncogene fibroblast growth factor receptor 3 confers dexamethasone resistance.
abstract: Translocations involving the immunoglobulin heavy-chain switch region and fibroblast growth factor receptor 3 (FGFR3) are identified in 10% to 15% of patients with myeloma. In previous research we overexpressed FGFR3 or the constitutively active FGFR3-TD mutant in an interleukin-6 (IL-6)-dependent murine myeloma cell line, B9. FGFR3-enhanced IL-6 responsiveness increased phosphorylation of STAT3 and up-regulated Bcl-x(L). Since Bcl-x(L) was up-regulated, we have tested FGFR3-expressing B9 cells for chemotherapy sensitivity. FGFR3 expression did not alter sensitivity to melphalan or doxorubicin. In contrast, B9 cells overexpressing FGFR3 were resistant to treatment with dexamethasone, a phenomenon successfully reversed using a Bcl-x(L) antisense oligonucleotide. These data demonstrate that the overexpression of FGFR3 in B9 cells confers resistance to dexamethasone but not to anthracyclines or alkylating agents, at least in part through the up-regulation of Bcl-x(L). This finding has potential implications for the use of chemotherapy in t(4;14)-positive myeloma.
authors.affiliation: Division of Experimental Therapeutics, Toronto General Research Institute, and the Department of Medical Oncology, Princess Margaret Hospital, Toronto, ON, Canada.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Pollett
authors.forename: Suzanne
authors.initials: S
authors.lastname: Trudel
authors.forename: Daniel
authors.initials: D
authors.lastname: Stern
authors.forename: Zhixiong H
authors.initials: ZH
authors.lastname: Li
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
mesh_terms: D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009194:Myeloma Proteins / Q000235:genetics; D009857:Oncogenes; D011505:Protein-Tyrosine Kinases; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000502:physiology; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics* / Q000502:physiology; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051020:bcl-X Protein
chemical_list: C494812:Bcl2l1 protein, mouse; D009194:Myeloma Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017468:Receptors, Fibroblast Growth Factor; D051020:bcl-X Protein; D003907:Dexamethasone; C496366:Fgfr3 protein, mouse; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3