Analysis of FGFR3 gene mutations in multiple myeloma patients with t(4;14)

Abstract

Summary. The t(4;14)(p16.3;q32) in multiple myeloma (MM) leads to an apparent deregulation of the FGFR3 and WHSC1/MMSET genes. FGFR3 mutations, known to be associated with genetic skeletal disorders, have also been identified in a few cases of MM (mainly cell lines) with t(4;14). We investigated FGFR3 mutations in a series of 53 MM cases; 11 cases with t(4;14) and FGFR3 overexpression were analysed using reverse transcription polymerase chain reaction, while the remaining cases were studied at DNA level. The Arg248Cys mutation, which is associated with some lethal forms of skeletal disorders, was found in one case with t(4;14). Our results indicate that FGFR3 mutations occur in only a small fraction of MM cases with t(4;14).

NF449 Is a Novel Inhibitor of Fibroblast Growth Factor Receptor 3 (FGFR3) Signaling Active in Chondrocytes and Multiple Myeloma Cells

“…Initial screenings performed at 5, 10, and 20 M scales identified a compound named NF449 as a potent antagonist of the FGF2/ FGFR3-inhibitory effect on RCS proliferation. 3 This effect was confirmed in detailed cell growth experiments, where 20 M NF449 caused significant rescue of the growth arrest phenotype without apparent cellular toxicity throughout its active concentration range (ϳ6 -30 M; Fig. 1A).…”

“…Because the CCL3 (MIP-1␣) and CCL4 (MIP-1␤) chemokines were previously identified as transcriptional targets of FGFR3 signaling in multiple myeloma (17), 3 we determined the effect of NF449 on the FGF2-mediated accumulation of the CCL3 and CCL4 transcripts. Real-time reverse transcription-PCR analysis showed the partial NF449-mediated rescue of the CCL3 and CCL4 accumulation induced by FGF2 treatment in the OPM2 cells (Fig.…”

“…Apart from cartilage, ϳ15% of patients suffering from multiple myeloma markedly up-regulate FGFR3 as a consequence of a t(4;14)(p16.3;q32) translocation, with a fraction of patients also harboring activating mutations in FGFR3, identical to those found in the skeletal dysplasias (2,3). Ectopic expression of FGFR3 enhances multiple myeloma cell proliferation and survival, demonstrating the oncogenic potential of FGFR3 (6).…”

“…To date, activating mutations in FGFR3 have been associated with several human disorders, such as skeletal dysplasias, multiple myeloma, and cervical and bladder carcinomas (1)(2)(3)(4).…”

FGFR3IIIS: a novel soluble FGFR3 spliced variant that modulates growth is frequently expressed in tumour cells

“…Where mutations of FGFR3 are frequent events, forexample, in bladder cancer (Cappellen et al, 1999;Billerey et al, 2001;van Rhijn et al, 2001;Sibley et al, 2001), nonsense mutations inserted within its coding region may result in altered splice site selection (Valentine, 1998). This is unlikely to be the case for the majority of cancers where mutations of FGFR3 are rare (Intini et al, 2001;Karoui et al, 2001;Sibley et al, 2001), although FGFR3 may be inactivated by aberrant-splicing and activation of cryptic splice donor sites (Jang et al, 2000). In this study we have identified and characterised a novel FGFR3IIIc variant, FGFR3IIIS, which is frequently expressed in tumorigenic but rarely in nontumorigenic cells.…”