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Ectopic expression of wild-type FGFR3 cooperates with MYC to accelerate development of B-cell lineage neoplasms.

The t(4;14) translocation in multiple myeloma (MM) simultaneously dysregulates two apparent oncogenes: fibroblast growth factor receptor 3 (FGFR3) controlled by the 3' immunoglobulin heavy chain enhancer on der(14) and MMSET controlled by the intronic Emu enhancer on der(4). Although all MM tumors and cell lines with a t(4;14) translocation have dysregulated MMSET, about 25% do not express FGFR3. Therefore, the function of dysregulated wild-type (WT) FGFR3 in the pathogenesis of MM remains unclear. We developed a murine transgenic (TG) model in which WT FGFR3 is overexpressed in B lymphoid cells. Although high levels of FGFR3 resulted in lymphoid hyperplasia in about one-third of older mice, no increase in tumorigenesis was observed. However, double TG FGFR3/Myc mice develop mature B lymphoma tumors that occur with a higher penetrance and shorter latency than in single TG Myc mice (P=0.006). We conclude that expression of high levels of WT FGFR3 can be oncogenic and cooperate with MYC to generate B lymphoid tumors. This suggests that dysregulated FGFR3 expression is likely to be essential at least for the early stages of pathogenesis of MM tumors that have a t(4;14) translocation.

Pubmed ID: 20393505

Authors

  • Zingone A
  • Cultraro CM
  • Shin DM
  • Bean CM
  • Morse HC
  • Janz S
  • Kuehl WM

Journal

Leukemia

Publication Data

June 10, 2010

Associated Grants

  • Agency: NCI NIH HHS, Id: P50CA097274
  • Agency: NCI NIH HHS, Id: R01 CA151354
  • Agency: NCI NIH HHS, Id: R01 CA151354-01
  • Agency: Intramural NIH HHS, Id:

Mesh Terms

  • Animals
  • Blotting, Southern
  • Blotting, Western
  • Female
  • Gene Expression Profiling
  • Genes, Immunoglobulin
  • Humans
  • Immunoenzyme Techniques
  • Immunophenotyping
  • Immunoprecipitation
  • Lymphoma, B-Cell
  • Male
  • Mice
  • Mice, Transgenic
  • Multiple Myeloma
  • Oligonucleotide Array Sequence Analysis
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • Receptor, Fibroblast Growth Factor, Type 3
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Markers, Biological