Fibroblast Growth Factor Receptor 3 and Multiple Myeloma

  • Victor Hugo Jiménez-Zepeda
  • A. Keith Stewart
Part of the Contemporary Hematology book series (CH)


Chromosomal translocations involving the immunoglobulin heavy chain (IgH) gene locus are found in 40% of patients with multiple myeloma (MM), a malignancy of terminally differentiated B cells.1, 2, 3 One of the most common translocations, t(4;14), seen in 15% of cases, is associated with a poor prognosis.4, 5, 6, 7 The molecular pathogenesis of t(4;14) is thought to involve aberrant immunoglobulin class-switching recombination, leading to a reciprocal translocation between chromosomes 14q32 and 4p16.3 that repositions fibroblast growth factor receptor 3 (FGFR3) to der(14) and creates a fusion gene with MM SET domain containing protein (MMSET) on der(4) under the influence of strong enhancers from the IgH region.8,9FGFR3 is one of a family of five tyrosine kinases through which fibroblast growth factors signal. These receptors are characterized by an extracellular domain with two or three immunoglobulin-like domains, a transmembrane domain, and a cytoplasmic tyrosine...


Multiple Myeloma Myeloma Cell Line Bone Marrow Plasma Cell Thanatophoric Dysplasia Primary Myeloma Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Bergsagei PL, Chesi M, Nardini E, et al. Promiscuous translocation into immunoglobulin heavy chain switch regions in multiple myeloma. Proc Natl Acad Sci USA.1996;93:13931–13936.CrossRefGoogle Scholar
  2. 2.
    Konigsberg R, Zojer N, Ackermann J, et al. Predictive role of interphase cytogenetics for survival of patients with multiple myeloma. J Clin Oncol. 2000;18:804–812.PubMedGoogle Scholar
  3. 3.
    Avet-Loiseau H, Facon T, Grosbois B, et al. Oncogenesis of multiple myeloma: 14q32 and 13 q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation. Blood. 2002;99:2185–2191.PubMedCrossRefGoogle Scholar
  4. 4.
    Moreau P, Facon T, Leleu X, et al. Recurrent 14q32 translocations determine the prognosis of multiple myeloma, especially in patients receiving intensive chemotherapy. Blood. 2002;100:1579–1583.PubMedCrossRefGoogle Scholar
  5. 5.
    Fonseca R, Blood E, Rue M, et al. Clinical biologic implications of recurrent genomic aberrations in myeloma. Blood. 2003;101:4569–4575.PubMedCrossRefGoogle Scholar
  6. 6.
    Keats JJ, Reiman T, Maxwell CA, et al. In multiple myeloma, t(4;14) (p16;32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood. 2003; 101:1520–1529.PubMedCrossRefGoogle Scholar
  7. 7.
    Chang H, Sloan S, Li D, et al. The t(4;14) is associated with poor prognosis in myeloma patients undergoing autologous stem cell transplant. Br J Haematol. 2004;125:64–68.PubMedCrossRefGoogle Scholar
  8. 8.
    Chesi M, Nardini E, Brents LA, 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. 1997;16:260–264.PubMedCrossRefGoogle Scholar
  9. 9.
    Chesi M, Nardini E, Urn RS, et al. The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene MMSET, resulting in lgH/MMSET hybrid transcripts. Blood. 1998;92:3025–3034.PubMedGoogle Scholar
  10. 10.
    Bergsagel PL and Kuehl WM. Chromosome translocations in multiple myeloma. Oncogene. 2001;20:5611–5622.PubMedCrossRefGoogle Scholar
  11. 11.
    Hallek M, Bergsagel PL and Anderson KC. Multiple myeloma: increasing evidence for a multistep transformation process. Blood. 1998;91:3.PubMedGoogle Scholar
  12. 12.
    Plowright EE, Li Z, Bergsagel PL, et al. Ectopic expression of fibroblast growth factor receptor 3 promotes myeloma cell proliferation and prevents apoptosis. Blood. 2000;95:992–998.PubMedGoogle Scholar
  13. 13.
    Cheng J, Ifor R, Lee B, et al. Constitutively activated FGFR3 mutants signal through PLC7-dependent and -independent pathways for hematopoietic transformation. Blood. 2005;106:328–337.CrossRefGoogle Scholar
  14. 14.
    Colvin JS, Bohne BA, Harding GW, McEwan DG and Ornitz DM. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nat Genet. 1996;12:390.PubMedCrossRefGoogle Scholar
  15. 15.
    Paterson JL, Li Z, Wen XY, et al. Preclinical studies of fibroblast growth factor receptor 3 as a therapeutic target in multiple myeloma. Br J Haematol. 2004;124:595–603.PubMedCrossRefGoogle Scholar
  16. 16.
    Trudel S, Ely S, Farooqi Y, et al. Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma. Blood. 2004;103:3521–3528.PubMedCrossRefGoogle Scholar
  17. 17.
    Trudel S, Li ZH, Wei E, et al. CHIR 258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood. 2005;105:2941–2948.PubMedCrossRefGoogle Scholar
  18. 18.
    Santra M, Zhan F, Tian E, et al. A subset of multiple myeloma harboring the t(4;14) (p16;q32) translocation lacks FGFR3 expression but maintains an lgH/MMSET fusion transcript. Blood. 2003;101:2374–2376.PubMedCrossRefGoogle Scholar
  19. 19.
    Dring AM, Davies FE, Fenton JA, et al. A global expression-based analysis of the consequences of the t(4;14) translocation in myeloma. Clin Cancer Res. 2004;10:5692–5701.PubMedCrossRefGoogle Scholar
  20. 20.
    Chang H, Stewart AK, Ying-Qi X, et al. Immunohistochemistry accurately predicts FGFR3 aberrant expression and t(4;14) in multiple myeloma. Blood. 2005;106:353–355.PubMedCrossRefGoogle Scholar
  21. 21.
    Passos-Bueno MR, Wilcox JR, Jabs EW, et al. Clinical spectrum of fibroblast growth factor receptor mutations. Hum Mutat. 1999;14:115–125.PubMedCrossRefGoogle Scholar
  22. 22.
    Boersma-Vreugdenhil GR, Kuipers J, Van Stralen E, et al. The recurrent translocation t(14;20) (q32;q12) in multiple myeloma results in aberrant expression of MAFB: a molecular and genetic analysis of the chromosomal breakpoint. Br J Haematol. 2004;126:355–363.PubMedCrossRefGoogle Scholar
  23. 23.
    Smadja NV, Leroux D, Soulier J, et al. Further cytogenetic characterization of multiple myeloma confirms that 14q32 translocations are a very rare event in hyperdiploid cases. Genes Chromosomes Cancer. 2003;38:234–239.PubMedCrossRefGoogle Scholar
  24. 24.
    Malgeri U, Baldini L, Perfetti V, et al. Detection of t(4;14) (p16.3;q32) chromosomal translocation in multiple myeloma by reverse transcription polymerase chain reaction analysis of lgH-MMSET fusion transcripts. Cancer Res. 2000;60:4058–4061.PubMedGoogle Scholar
  25. 25.
    Fabris S, Agnelli L, Mattioli M, et al. Characterization of oncogene dysregulation in multiple myeloma by combined FISH and DNA microarray analyses. Genes Chromosomes Cancer. 2005;42:117–127.PubMedCrossRefGoogle Scholar
  26. 26.
    Keats JJ, Reiman T, Belch AR, et al. Ten years and counting: so what do we know about t(4:14) (p16;q32) multiple myeloma. Leuk Lymphoma. 2006;47:2289–2300.PubMedCrossRefGoogle Scholar
  27. 27.
    Webster MK and Donoghue DJ. FGFR activation in skeletal disorders: too much of a good thing. Trends Genet. 1997;13:178–182.PubMedCrossRefGoogle Scholar
  28. 28.
    Ishikawa H, Tsuyama N, Liu S, et al. Accelerated proliferation of myeloma cells by interleukin-6 cooperating with fibroblast growth factor receptor 3-mediated signals. Oncogene. 2005;24(41):6328–6332.PubMedCrossRefGoogle Scholar
  29. 29.
    Firme L and Bush AB. FGF signaling inhibits the proliferation of human myeloma cells and reduces c-myc expression. BMC Cell Biol. 2003;4:17.PubMedCrossRefGoogle Scholar
  30. 30.
    Sleeman M, Fraser J, McDonald M, et al. Identification of a new fibroblast growth factor receptor, FGFR5. Gene. 2001;271:171–182.PubMedCrossRefGoogle Scholar
  31. 31.
    Elsheikh E, Green AR, Lambros MB, et al. FGFR1 amplification in breast carcinomas: a chromogenic in situ hybridisation analysis. Breast Cancer Res. 2007;9(2):R23.CrossRefGoogle Scholar
  32. 32.
    Hernadez S, Toll A, Baselga E, et al. Fibroblast growth factor receptor 3 mutations in epidermal nevi and associated low grade bladder tumors. J Invest Dermatol. 2007;127(7):1664–1666.Google Scholar
  33. 33.
    Patstone G, Pasquale EB and Maher PA. Different members of the fibroblast growth factor receptor family are specific to distinct cell types in the developing chicken embryo. Dev Biol. 1993;155:107–123.PubMedCrossRefGoogle Scholar
  34. 34.
    Vidrich A, Buzan JM, Lb C, et al. Fibroblast growth factor receptor-3 is expressed in undifferentiated intestinal epithelial cells during murine crypt morphogenesis. Dev Dyn. 2004;230:114–123.PubMedCrossRefGoogle Scholar
  35. 35.
    Chellaiah AT, McEwen DG, Werner S, et al. Fibroblast growth factor receptor (FGFR) 3. Alternative splicing in immunoglobulin-like domain Ill creates a receptor highly specific for acidic FGF/FGF-1. J Biol Chem. 1994;269:11620–11627.PubMedGoogle Scholar
  36. 36.
    Pringle NP, Yu WP, Howell M, et al. Fgfr3 expression by astrocytes and their precursors: evidence that astrocytes and oligodendrocytes originate in distinct neuroepithelial domains. Development. 2003;130:93–102.PubMedCrossRefGoogle Scholar
  37. 37.
    Peters K, Ornitz D, Werner S and Williams L. Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis. Dev Biol. 1993;155:423–430.PubMedCrossRefGoogle Scholar
  38. 38.
    Govindarajan V and Overbeek PA. Secreted FGFR3, but not FGFR1, inhibits lens fiber differentiation. Development. 2001;128:1617–1627.PubMedGoogle Scholar
  39. 39.
    Deng C, Wynshaw-Boris A, Zhou F, et al. Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell. 1996;84:911–921.PubMedCrossRefGoogle Scholar
  40. 40.
    Richelda R, Ronchetti D, Baldini L, et al. A novel chromosomal translocation t(4;14) (p16.3;q32) in multiple myeloma involves the fibroblast growth factor receptor 3 gene. Blood. 1997;90:4062–4070.PubMedGoogle Scholar
  41. 41.
    Cappeflen D, De Oliveira C, Ricol D, et al. Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nat Genet. 1999;23:18–20.Google Scholar
  42. 42.
    Hata H. Bone lesions and macrophage inflammatory protein-1 alpha (MIP-1a) in human multiple myeloma. Leuk Lymphoma. 2005;46:967–972.PubMedCrossRefGoogle Scholar
  43. 43.
    Jang H, Shin KH and Park JG. Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers. Cancer Res. 2001;65:3541–3543.Google Scholar
  44. 44.
    Naimi B, Latil A, Berthon P and Cussenot O. No evidence for fibroblast growth factor receptor 3 (FGFR-3) R248C/S249C mutations in human prostate cancer. Int J Cancer. 2000;87:455–456.PubMedCrossRefGoogle Scholar
  45. 45.
    Karoui M, Hofmann-Radvanyi H, Zimmermann U, et al. No evidence of somatic FGFR3 mutation in various types of carcinoma. Oncogene. 2001;20:5059–5061.PubMedCrossRefGoogle Scholar
  46. 46.
    Sibley K, Stern P and Knowles MA Frequency of fibroblast growth factor receptor 3 mutations in sporadic tumours. Oncogene. 2001;20:4416–4418.PubMedCrossRefGoogle Scholar
  47. 47.
    Avet-Loiseau H, Facon T, Daviet A, et al. 14q32 translocations and monosomy 13 observed in monoclonal gammopathy of undetermined significance delineate a multistep process for the oncogenesis of multiple myeloma. lntergroupe Francophone du Myelome. Cancer Res. 1999;59:4546–4550.PubMedGoogle Scholar
  48. 48.
    Sibley K, Fenton JA, Dring AM, et al. A molecular study of the t(4;14) in multiple myeloma. Br J Haematol. 2002;118:514–520.PubMedCrossRefGoogle Scholar
  49. 49.
    Soverini S, Terragna C, Testoni N, et al. Novel mutation and RNA splice variant of fibroblast growth factor receptor 3 in multiple myeloma patients at diagnosis. Haematologica. 2002;87:1036–1040.PubMedGoogle Scholar
  50. 50.
    Onwuazor ON, Wen XY, Wang DY, et al. Mutation, SNP, and isoform analysis of fibroblast growth factor receptor 3 (FGFR3) in 150 newly diagnosed multiple myeloma patients. Blood. 2003;102:772–773.PubMedCrossRefGoogle Scholar
  51. 51.
    Chesi M, Brents LA, Ely SA, et al. Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma. Blood. 2001;98:1271–1272.CrossRefGoogle Scholar
  52. 52.
    Li Z, Zhu YX, Plowright EE, et al. The myeloma-associated oncogene fibrob-last growth factor receptor 3 is transforming in hematopoietic cells. Blood. 2001;97:2413–2419.PubMedCrossRefGoogle Scholar
  53. 53.
    Chandesris MO, Soulier J, Labaume S, et al. Detection and follow-up of fibroblast growth factor receptor 3 expression on bone marrow and circulating plasma cells by flow cytometry in patients with t(4;14) multiple myeloma. Br J Haematol. 2007;36(4):609–614.CrossRefGoogle Scholar
  54. 54.
    Masih-Khan E, Trudel S, Heise C, et al. MIP-lalpha (CCL3) is a downstream target of FGFR3 signalling in multiple myeloma. Blood. 2006;108(10):3465–3471.PubMedCrossRefGoogle Scholar
  55. 55.
    Roodman GD and Choi SJ. MIP-1 alpha and myeloma bone disease. Cancer Treat Res. 2004;118:83–100.PubMedGoogle Scholar
  56. 56.
    Terpos E, Politou M, Szydlo R, Goldman JM, Apperley JF and Rahemtulla A Serum levels of macrophage inflammatory protein-1 alpha (MIP-l alpha) correlate with the extent of bone disease and survival in patients with multiple myeloma. Br J Haematol. 2003;123:106–109.PubMedCrossRefGoogle Scholar
  57. 57.
    Lentzsch S, Chatterjee M, Gries M, et al. P13-K'AKT/FKHR and MAPK signaling cascades are redundantly stimulated by a variety of cytokines and contribute independently to proliferation and survival of multiple myeloma cells. Leukemia. 2004;18:1883–1890.PubMedCrossRefGoogle Scholar
  58. 58.
    Zhu L, Somlo G, Zhou B, et al. Fibroblast growth factor receptor 3 inhibition by short hairpin RNAs leads to apoptosis in multiple myeloma. Mol Cancer Ther. 2005;4:787–798.PubMedCrossRefGoogle Scholar
  59. 59.
    Lossos IS, Czerwinski DK, Alizadeh AA, et al. Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N Engl J Med. 2004;350:1828–1837.PubMedCrossRefGoogle Scholar
  60. 60.
    Kuehl WM and Bergsagel PL. Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer. 2002;2:175–187.PubMedCrossRefGoogle Scholar
  61. 61.
    Fonseca R, Barlogie B, Bataille R, et al. Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res. 2004;64:1546–1558.PubMedCrossRefGoogle Scholar
  62. 62.
    Bergsaget PL, Kuehl WM, Zhan F, et al. Cyclin D dysregulation: an early unifying pathogenic event in multiple myeloma. Blood. 2005;106:296–303.CrossRefGoogle Scholar
  63. 63.
    Poulsen TS, Silahtaroglu AN, Gisselo CG, et al. Detection of illegitimate rearrangements within the immunoglobulin light chain loci in B cell malignancies using end sequenced probes. Leukemia. 2002;16:2148–2155.PubMedCrossRefGoogle Scholar
  64. 64.
    Cavo M, Terragna C, Renzulli M, et al. Poor outcome with front-line autologous transplantation in t(4;14) multiple myeloma: low complete remission rate and short duration of remission. J Clin Oncol. 2006Jan 20;24(3):e4–e5.CrossRefGoogle Scholar
  65. 65.
    Mulligan G, Mitsiades C, Bryant B, et al. Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib. Blood. 2007;109:3177–3188.PubMedCrossRefGoogle Scholar
  66. 66.
    Moreau P, Attal M, Garban F, et al. Heterogeneity of t(4;14) in multiple myeloma. Long-term follow-up of 100 cases treated with tandem transplantation in IFM99 trials.Leukemia. 2007 July 12; [Epub ahead of print].Google Scholar
  67. 67.
    Jaksic W, Trudel S, Chang H, et al. Clinical outcomes in t(4;14) multiple myeloma: a chemotherapy-sensitive disease characterized by rapid relapse and alkylating agent resistance. J Clin Oncol. 2005 Oct 1;23(28):7069–7073.CrossRefGoogle Scholar
  68. 68.
    Gutierrez NC, Castellanos MV, MartIn ML, et al. Prognostic implications of genetic abnormalities in multiple myeloma undergoing autologous stem cell transplantation: t(4;14) is the most relevant adverse prognostic factor, whereas RB deletion as a unique abnormality is not associated with adverse prognosis. Leukemia. 2007;21:143–150.PubMedCrossRefGoogle Scholar
  69. 69.
    Gertz MA, Lacy MQ, Dispenzieri A, et al. Clinical implications of t(11;14) (q13;q32), t(4;14) (p16.2,q32), and -17p13 in myeloma patients treated with high-dose therapy. Blood. 2005;106:2837–2840.PubMedCrossRefGoogle Scholar
  70. 70.
    Avet-Loiseau H, Attal M, Moreau P, et al. Genetic abnormalities and survival in multiple myeloma: the experience of the lntergroupe Francophone du Myelome. Blood. 2007 Apr 15;109(8):3489–3495.PubMedCrossRefGoogle Scholar
  71. 71.
    Chang H, Tribu Y, Qi X, et al. Bortezomib therapy response is independent of cytogenetic abnormalities in relapsed/refractory multiple myeloma. Leuk Res. 2006 Sep 20; [Epub ahead of print].Google Scholar
  72. 72.
    Mateos MV, Hernández JM, Hernández MT, et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multi-center phase I/II study. Blood. 2006;108:2165–2172.PubMedCrossRefGoogle Scholar
  73. 73.
    Bahlis NJ, Mansoor A, Lategan JC, et al. Lenalidomide overcomes poor prognosis conferred by deletion of chromosome 13 and t(4;14) in multiple myeloma: MMOI6 Trial. Blood. 2006;108:(Abstract).Google Scholar
  74. 74.
    Grand EK, Chase AJ, Heath C, et al. Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by SU5402 and PD173074. Leukemia. 2004;18:962–966.PubMedCrossRefGoogle Scholar
  75. 75.
    Trudel S, Stewart AK, Rom E, et al. The inhibitory anti-FGFR3 antibody, PRO-001, is cytotoxic to t(4;14) multiple myeloma cells. Blood. 2006 May 15;107(10):4039–4046.PubMedCrossRefGoogle Scholar
  76. 76.
    Andrejauskas-Buchdunger E and Regenass U. Differential inhibition of the epidermal growth factor-, platelet-derived growth factor-, and protein kinase C-mediated signal transduction pathways by the staurosporine derivative CGP 41251. Cancer Res. 1992;52(19):5353–5358.PubMedGoogle Scholar
  77. 77.
    Fabbro D, Ruetz S, Bodis S, et al. PKC412—a protein kinase inhibitor with a broad therapeutic potential. Anticancer Drug Des. 2000;15:17–28.PubMedGoogle Scholar
  78. 78.
    Weisberg E, Boulton C, Kelly LM, et al. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC4I 2. Cancer Cell. 2002;1:433–443.PubMedCrossRefGoogle Scholar
  79. 79.
    Estey EH, Fisher T, Giles F, et al. Effect of circulating blasts at time of complete remission on subsequent relapse-free survival time in newly diagnosed AML. Blood. 2003;102:3097–3099.PubMedCrossRefGoogle Scholar
  80. 80.
    Stone RM, DeAngelo DJ, KIlmek V, et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005 Jan 1;105(1):54–60.PubMedCrossRefGoogle Scholar
  81. 81.
    Chen J, DeAngelo DJ, Kutok JL, et al. PKC412 inhibits the zinc finger 198-fibrob-last growth factor receptor 1 fusion tyrosine kinase and is active in treatment of stem cell myeloproliferative disorder. Proc Natl Acad Sci USA. 2004;101:14479–14484.PubMedCrossRefGoogle Scholar
  82. 82.
    Chen J, Lee BH, Williams IR, et al. FGFR3 as a therapeutic target of the small molecule inhibitor PKC4I2 in hematopoietic malignancies. Oncogene. 2005 Dec 15; 24(56):8259–8267.PubMedCrossRefGoogle Scholar
  83. 83.
    Dewald GW, Therneau T, Larson D, Relationship of patient survival and chromosome anomalies detected in metaphase and/or interphase cells at diagnosis of myeloma. Blood. 2005 Nov 15; 106(10):3553–3558.PubMedCrossRefGoogle Scholar
  84. 84.
    Chiecchio L, Protheroe RK, Ibrahim AH, Deletion of chromosome 13 detected by conventional cytogenetics is a critical prognostic factor in myeloma. Leukemia. 2006 Sep; 20(9):1610–1617.PubMedCrossRefGoogle Scholar
  85. 85.
    Nakazawa N, Nishida K, Tamura A, lnterphase detection of t(4;14) (p16.3;q32) by in situ hybridization and FGFR3 overexpression in plasma cell malignancies. Cancer Genet Cytogenet. 2000;117:89–96.PubMedCrossRefGoogle Scholar
  86. 86.
    Rasmussen T, Theligaard-Monch K, Hudlebusch HR, Occurrence of dysregulated oncogenes in primary plasma cells representing consecutive stages of myeloma pathogenesis: indications for different disease entities. Br J Haematol. 2003;123:253–262.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Victor Hugo Jiménez-Zepeda
    • 1
  • A. Keith Stewart
    • 2
  1. 1.Department of Hematological MalignanciesMayo Clinic College of MedicineScottsdaleUSA
  2. 2.Mayo Clinic College of MedicineScottsdaleUSA

Personalised recommendations