Overexpression of the myeloma-associated oncogene fibroblast growth factor receptor 3 confers dexamethasone resistance.
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.
Pollett
Jonathan B
JB
Division of Experimental Therapeutics, Toronto General Research Institute, and the Department of Medical Oncology, Princess Margaret Hospital, Toronto, ON, Canada.
Trudel
Suzanne
S
Stern
Daniel
D
Li
Zhixiong H
ZH
Stewart
A Keith
AK
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
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