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 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.