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Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3

Abstract

Dysregulation of oncogenes by translocation to the IgH locus (14q32) is a seminal event in the pathogenesis of B-cell tumours1. In multiple myeloma (MM), translations to the IgH locus have been reported at an incidence of 20–60%. For most translocations, the partner chromosome is unknown (14q+); for the others, a diverse array of chromosomal partners have been identified, with 11q13 (cyclin D1) the only chromosome that is frequently involved2–6. Recently, we developed a Southern-blot assay that detects translocation breakpoint fragments in most MM tumours, including those with no translocation detected by conventional karyotyping6. In a continuing analysis of translocations in 21 myeloma cell lines and primary tumours, we show that the novel, karyotypically silent translocation t(4;14)(p16.3;q32.3) is present in five lines and at least three of ten primary tumours. The chromosome-4 breakpoints are clustered in a 70-kb region centromeric to the f ibroblast growth factor receptor 3 gene (FGFR3), the apparent dysregulated oncogene. Two lines and one primary tumour with this translocation selectively express an FGFR3 allele containing activating mutations identified previously in thanatophoric dwarfism. We propose that after the t(4;14) translocation, somatic mutation during tumour progression frequently generates an FGFR3 protein that is active in the absence of ligand.

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References

  1. Korsmeyer, S.J. Chromosomal translations in lymphoid malignancies reveal novel proto-oncogenes. Annu. Rev. Immunol. 10, 785–607 (1992).

    Article  CAS  PubMed  Google Scholar 

  2. Taniwaki, M. et al. Nonrandom chromosomal rearrangements of 14q32.3 and 19p13.3 and preferential deletion of 1p in 21 patients with multiple myeloma and plasma cell leukemia. Blood 84, 2283–2290 (1994).

    CAS  PubMed  Google Scholar 

  3. Sawyer, J.R., Waldron, J.A., Jagannath, S. & Barlogie, B. Cytogenetic findings in 200 patients with multiple myeloma. Cancer Genet. Cytogenet. 82, 41–49 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. Lai, J.L. et al. Improved cytogenetics in multiple-myeloma—a study of 151 patients including 117 patients at diagnosis. Blood 85, 2490–2497 (1995).

    CAS  PubMed  Google Scholar 

  5. Chesi, M. et al. Dysregulation of Cyclin D1 by translocation into an IgH gamma switch region in two multiple myeloma cell lines. Blood 88, 674–681 (1996).

    CAS  PubMed  Google Scholar 

  6. Bergsagel, P.L. et al. Promiscuous translations into IgH switch regions in multiple myeloma. Proc. Natl. Sci. Acad. USA 93, 13931–13936 (1996).

    Article  CAS  Google Scholar 

  7. Baxendale, S. et al. A cosmid contig and high resolution restriction map of the 2 megabase region containing the Huntington's disease gene. Nature Genet. 4, 181–186 (1993).

    Article  CAS  PubMed  Google Scholar 

  8. Keegan, K., Johnson, D., William, L.T. & Hayman, M.J. Isolation of an additional member of the fibroblast growth factor receptor family, FGFR-3. Proc. Natl. Acad Sci. USA 88, 1095–1099(1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Keegan, K., Meyer, S. & Hayman, M.J. Structural and biosynthetic characterization of the fibroblast growth factor receptor 3 (FGFR-3) protein. Oncogene 6, 2229–2236 (1991).

    CAS  PubMed  Google Scholar 

  10. Muenke, M. & Schell, U. Fibroblast-growth-factor-receptor mutations in human sketetal disorders. Trends Genet. 11, 308–313 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Naski, M.C., Wang, Q., Xu, J. & Ornitz, D.M. Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia. Nature Genet. 13, 233–237 (1996).

    Article  CAS  PubMed  Google Scholar 

  12. Webster, M.K., D'Avis, P.Y., Robertson, S.C. & Donoghue, D.J. Profound ligand-independent kinase activation of fibroblast growth factor receptor 3 by the activation loop mutation responsible for a lethal skeletal dysplasia, thanatophoric dysplasia type II. Mol. Cell. Biol. 16, 4081–4087 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Webster, M.K. & Donoghue, D.J. Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia. EMBO J. 15, 520–527 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rousseau, F. et al. Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism typeI (TD1). Hum. Mol. Genet. 5, 509–512 (1996).

    Article  CAS  PubMed  Google Scholar 

  15. Francomano, C.A. et al. A new skeletal dysplasia with severe tibial bowing, profound developmental delay and acanthosis nigricans is caused by a Lys 650 Met mutation in fibroblast growth factor receptor 3 (FGFR3). Am. J. Hum. Genet. 59, A25 (1996).

    Google Scholar 

  16. Tavormina, P.L. et al. Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nature Genet. 9, 321–328 (1995).

    Article  CAS  PubMed  Google Scholar 

  17. Williams, M.E., Swerdlow, S.H. & Meeker, T.C. Chromosome t(11;14)(q13;q32) breakpoints in centrocytic lymphoma are highly localized at the bcl-1 major translocation cluster. Leukemia 7, 1437–1440 (1993).

    CAS  PubMed  Google Scholar 

  18. Tsujimoto, Y. et al. Clustering of breakpoints on chromosome 11 in human B-cell neoplasms with the t(11;14) chromosome translocation. Nature 315, 340–343 (1985).

    Article  CAS  PubMed  Google Scholar 

  19. de Boer, C.J. et al. Multiple breakpoints within the BCL-1 locus in B-cell lymphoma: rearrangements of the cyclin D1 gene. Cancer Res. 53, 4148–4152 (1993).

    CAS  PubMed  Google Scholar 

  20. Mason, I.J. The ins and outs of fibroblast growth factors. Cell 78, 547–552 (1994).

    Article  CAS  PubMed  Google Scholar 

  21. Su, W.S. et al. Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism. Nature 386, 288–292 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Colvin, J.S., Bohne, B.A., Harding, G.W., McEwen, D.G. & Ornitz, D.M. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nature Genet. 12, 390–397 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Deng, C., Wynshaw-Boris, A., Zhou, F., Kuo, A. & Leder, P. Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell 84, 911–921 (1996).

    Article  CAS  PubMed  Google Scholar 

  24. Ornitz, D.M. & Leder, P. Ligand specificity and heparin dependence of fibroblast growth factor receptors 1 and 3. J. Biol. Chem. 267, 16305–16311 (1992).

    CAS  PubMed  Google Scholar 

  25. Caligaris-Cappio, F. et al. Role of bone marrow stromal cells in the growth of human multiple myeloma. Blood 77, 2688–2693 (1991).

    CAS  PubMed  Google Scholar 

  26. Allouche, M. Basic fibroblast growth factor and hematopoiesis. Leukemia 9, 937–942 (1995).

    CAS  PubMed  Google Scholar 

  27. Shiang, R. et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78, 335–342 (1994).

    Article  CAS  PubMed  Google Scholar 

  28. Johnston, C.L., Cox, H.C., Gomm, J.J. & Coombes, R.C. Fibroblast growth factor receptors (FGFRs) localize in different cellular compartments. J. Biol. Chem. 270, 30643–30650 (1995).

    Article  CAS  PubMed  Google Scholar 

  29. Schröck, E. et al. Multicolor spectral karyotyping of human chromosomes. Science 273, 494–497 (1996).

    Article  PubMed  Google Scholar 

  30. Kuehl, W.M., Brents, L.A., Chesi, M. & Bergsagel, P.L. Selective expression of one c-myc allele in two human myeloma cell lines. Cancer Res. 56, 4370–4373 (1996).

    CAS  PubMed  Google Scholar 

  31. Davis, L.G., Kuehl, W.M. & Battey, J.F., Methods in Molecular Biology (Appleton & Lange, Norwalk, Connecticut, 1994).

    Google Scholar 

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Correspondence to W. Michael Kuehl.

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Chesi, M., Nardini, E., Brents, L. et al. Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nat Genet 16, 260–264 (1997). https://doi.org/10.1038/ng0797-260

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