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Animal Models

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

Abstract

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 Eμ 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.

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Acknowledgements

We thank Marta Chesi (Mayo Clinic, Scottsdale, AZ) for providing immunohistochemistry (Figures 1c–f). This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (WMK), and National Institute of Allergy and Infectious Diseases (HCM), and Award Number P50CA097274 from the National Cancer Institute (SJ).

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Correspondence to W M Kuehl.

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Zingone, A., Cultraro, C., Shin, DM. et al. Ectopic expression of wild-type FGFR3 cooperates with MYC to accelerate development of B-cell lineage neoplasms. Leukemia 24, 1171–1178 (2010). https://doi.org/10.1038/leu.2010.50

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  • DOI: https://doi.org/10.1038/leu.2010.50

Keywords

  • FGFR3
  • Myc
  • lymphoma
  • multiple myeloma
  • oncogene

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