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.
Zingone
A
A
Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20889-5105, USA.
Cultraro
C M
CM
Shin
D-M
DM
Bean
C M
CM
Morse
H C
HC
Janz
S
S
Kuehl
W M
WM
D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015139:Blotting, Southern; D015153:Blotting, Western; D005260:Female; D020869:Gene Expression Profiling; D005803:Genes, Immunoglobulin; D006801:Humans; D007124:Immunoenzyme Techniques; D016130:Immunophenotyping; D047468:Immunoprecipitation; D016393:Lymphoma, B-Cell / Q000209:etiology* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009101:Multiple Myeloma / Q000209:etiology* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D014408:Biomarkers, Tumor; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3
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