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A novel mutation involving the carboxy terminal region of the FGFR3 gene in a multiple myeloma patient with t(4;14)

Leukemia volume 16, pages 1201–1202 (2002)Cite this article

The t(4;14)(p16.3;q32) chromosomal translocation in MM leads to the apparent deregulation of the fibroblast growth-factor receptor 3 (FGFR3) gene and the novel WHSC1/MMSET gene, whose 5′ untranslated region lies approximately 50 kb centromeric of FGFR3 on 4p16.1,2,3 We have recently demonstrated that this lesion occurs in approximately 20% of MM patients.4,5 Interestingly, FGFR3 gene mutations known to be associated with severe forms of dominant human skeletal disorders, such as thanatophoric dysplasia (TD) type I and II,6 have also been identified in some MM tumors with t(4;14): the Y373C mutation in the KMS-11 cell line,1,2 the K650E mutation in the OPM-2 cell line, and the K650M mutation in a primary tumor.1 Using a combination of RT-PCR, SSCP and direct DNA sequencing, we have recently investigated a panel of 11 primary t(4;14) MM tumors overexpressing a deregulated FGFR3 gene, and found only one mutated case (a A248C mutation associated with TDI).7

Three distinct missense mutations in the FGFR3 termination codon have been reported in five fetuses affected by TDI.10 These mutations were expected to produce a FGFR3 protein elongated by 141 amino acids as the mRNA continues through the 3′ untranslated 423 bp up to the same in-frame putative stop codon (nt 2881–2883 in Figure 1b). It was suggested that this would result in a highly hydrophobic domain with an α-helix structure at the carboxy-terminal end of the elongated protein. More recently, Chesi et al.11 reported the presence of an in-frame deletion of 42 bp encompassing the normal stop codon (codon 807) in the MM5.1 myeloma cell line, which gave rise to a putative protein elongated by 127 amino acids and ending at the same in-frame stop codon (Figure 1b).11 These authors also demonstrated that this putative protein could induce transformed foci in NIH3T3 cells in vitro, thus suggesting that protein elongation is a strong, albeit unknown mechanism, of FGFR3 activation. Our data further suggest that this mechanism is recurrent within the spectrum of FGFR3 mutations in MM.

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Figure 1

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Acknowledgements

This work was supported by grants from the Associazione Italiana Ricerca sul Cancro (AIRC) (to AN), the Ministero della Sanità to Ospedale Maggiore IRCCS and MURST 1999 No. 9906038391–010.

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  1. Department of Hematology, Hematology 1, IRCCS Ospedale Maggiore, Milan, Italy

    D Intini, L Baldini, L Lombardi & A Neri

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  1. D Intini
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Intini, D., Baldini, L., Lombardi, L. et al. A novel mutation involving the carboxy terminal region of the FGFR3 gene in a multiple myeloma patient with t(4;14). Leukemia 16, 1201–1202 (2002). https://doi.org/10.1038/sj.leu.2402502

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