Deregulated FGFR3 mutants in multiple myeloma cell lines with t(4;14): comparative analysis of Y373C, K650E and the novel G384D mutations.

摘要: The t(4;14)(p16.3;q32) chromosomal translocation occurs in approximately 20% of multiple myelomas (MM) and leads to the apparent deregulation two genes located on 4p16.3: fibroblast growth factor receptor 3 (FGFR3) putative transcription WHSC1/MMSET. Interestingly, FGFR3 mutations known be associated with autosomal dominant human skeletal disorders have also been found some MM cell lines t(4;14) but their pathogenetic role is still controversial. Since may represent useful models for investigating effects deregulated mutants MM, we analysed expression, activation, signaling pathways oncogenic potential three identified so far: Y373C K650E KMS-11 OPM-2 respectively, novel G384D mutation here KMS-18 line. All present a heterozygous gene transcribe mutated allele; unlike (which express IIIc isoform), line expresses prevalently isoform IIIb. We demonstrated that, under serum-starved conditions, cells appreciable levels phosphorylated indicating constitutive activation receptors; addition aFGF ligand further increased level phosphorylation. Conversely, mutant does not seem constitutively activated since it was only presence ligand. In all lines, ligand-stimulated MAP kinase pathway did apparently involve either STAT1 or STAT3 cascades. However, when transfected 293T cells, G384D, like K650E, capable activating MAPK, condition. Finally, focus formation assay NIH3T3 FGFR3-expressing plasmid vectors showed that (albeit at different levels) wild-type receptor, can induce transformed foci. Overall, our results support idea are graded terms capability, thus suggesting they play critical tumor progression patients t(4;14).