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A Novel Chromosomal Translocation t(4; 14)(p16.3; q32) in Multiple Myeloma Involves the Fibroblast Growth-Factor Receptor 3 Gene
Raffaella Richelda,
Domenica Ronchetti,
Luca Baldini,
Lilla Cro,
Luigi Viggiano,
Rosalia Marzella,
Mariano Rocchi,
Takemi Otsuki,
Luigia Lombardi,
Anna Teresa Maiolo, and
Antonino Neri
From the Laboratorio di Ematologia Sperimentale e Genetica Molecolare, Servizio di Ematologia, Università degli Studi di Milano, Ospedale Maggiore IRCCS, Milano; Istituto di Genetica, Università di Bari, Bari, Italy; and the Department of Hygiene, Kawasaki Medical School, Okayama, Japan.
Chromosomal translocations involving the immunoglobulin heavy chain (IGH) locus at chromosome 14q32 represent a common mechanism of oncogene activation in lymphoid malignancies. In multiple myeloma (MM), the most consistent chromosomal abnormality is the 14q+ marker, which originates in one third of cases through a t(11; 14)(q13; q32) chromosomal translocation; in the remaining cases, the identity of the partner chromosomes has not been well established. We used a Southern blot approach based on the linkage analysis of the joining (J) and the constant (C) µ,  , and  regions to detect cases bearing IGH switch-mediated chromosomal translocations. We evaluated DNA of 88 nonkaryotyped patients with MM (78 cases) or plasma cell leukemia (PCL) (10 cases) and found the presence of "illegitimate" rearranged IGH fragments (no comigration between the J and C regions) in 21 cases. To confirm this analysis, we cloned the illegitimate rearranged fragments from three samples, and the molecular and fluorescent in situ hybridization (FISH) analyses indicated the presence of chromosomal translocations juxtaposing a switch IGH region to sequences from chromosomes 11q13 (one PCL case) or 4p16.3 (two MM cases). Interestingly, the breakpoints on 4p16.3 occurred about 14 kb apart in a genomic region located approximately 50 kb centromeric to the fibroblast growth-factor receptor 3 (FGFR3) gene. Moreover, Southern blot analysis using 4p16.3 genomic probes detected a rearrangement in an additional MM tumor. FISH analysis of the MM-derived KMS-11 cell line, reported to be associated with a t(4; 14)(p16.3; q32), showed that the FGFR3 gene was translocated on 14q32. High levels of FGFR3 mRNA expression were observed in the cloned MM tumors and KMS-11 cell line, but not in the cases that were apparently negative for this lesion. Furthermore, a point mutation at codon 373 in the transmembrane domain of the FGFR3 gene resulting in an amino acid substitution (Tyr  Cys) was detected in the KMS-11 cell line. These findings indicate that the t(4; 14)(p16.3; q32) represents a novel, recurrent chromosomal translocation in MM, and suggest that the FGFR3 gene may be the target of this abnormality and thus contribute to tumorigenesis in MM.
Blood, Vol. 90 No. 10 (November 15), 1997:
pp. 4062-4070
© 1997 by The American Society of Hematology.
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Hum. Mol. Genet.,
July 15, 2009;
18(14):
2609 - 2621.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Salazar, T. Kashiwada, P. Krejci, P. Muchowski, D. Donoghue, W. R. Wilcox, and L. M. Thompson
A novel interaction between fibroblast growth factor receptor 3 and the p85 subunit of phosphoinositide 3-kinase: activation-dependent regulation of ERK by p85 in multiple myeloma cells
Hum. Mol. Genet.,
June 1, 2009;
18(11):
1951 - 1961.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. L.R. Brito, B. Walker, M. Jenner, N. J. Dickens, N. J.M. Brown, F. M. Ross, A. Avramidou, J. A.E. Irving, D. Gonzalez, F. E. Davies, et al.
MMSET deregulation affects cell cycle progression and adhesion regulons in t(4;14) myeloma plasma cells
Haematologica,
January 1, 2009;
94(1):
78 - 86.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. N. Meyer, C. W. McAndrew, and D. J. Donoghue
Nordihydroguaiaretic Acid Inhibits an Activated Fibroblast Growth Factor Receptor 3 Mutant and Blocks Downstream Signaling in Multiple Myeloma Cells
Cancer Res.,
September 15, 2008;
68(18):
7362 - 7370.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Dutt, H. B. Salvesen, T.-H. Chen, A. H. Ramos, R. C. Onofrio, C. Hatton, R. Nicoletti, W. Winckler, R. Grewal, M. Hanna, et al.
Drug-sensitive FGFR2 mutations in endometrial carcinoma
PNAS,
June 24, 2008;
105(25):
8713 - 8717.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. VanDijken, G. V. Kaigala, J. Lauzon, A. Atrazhev, S. Adamia, B. J. Taylor, T. Reiman, A. R. Belch, C. J. Backhouse, and L. M. Pilarski
Microfluidic Chips for Detecting the t(4;14) Translocation and Monitoring Disease during Treatment Using Reverse Transcriptase-Polymerase Chain Reaction Analysis of IgH-MMSET Hybrid Transcripts
J. Mol. Diagn.,
July 1, 2007;
9(3):
358 - 367.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Dispenzieri, S. V. Rajkumar, M. A. Gertz, M. Q. Lacy, R. A. Kyle, P. R. Greipp, T. E. Witzig, J. A. Lust, S. J. Russell, S. R. Hayman, et al.
Treatment of Newly Diagnosed Multiple Myeloma Based on Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART): Consensus Statement
Mayo Clin. Proc.,
March 1, 2007;
82(3):
323 - 341.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Ren, D. Raina, W. Chen, G. Li, L. Huang, and D. Kufe
MUC1 Oncoprotein Functions in Activation of Fibroblast Growth Factor Receptor Signaling
Mol. Cancer Res.,
November 1, 2006;
4(11):
873 - 883.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. R. Cook, M. Hartke, J. Pettay, and R. R. Tubbs
Fluorescence in Situ Hybridization Analysis of Immunoglobulin Heavy Chain Translocations in Plasma Cell Myeloma Using Intact Paraffin Sections and Simultaneous CD138 Immunofluorescence
J. Mol. Diagn.,
September 1, 2006;
8(4):
459 - 465.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. W. Finch and J. S. Rubin
Keratinocyte growth factor expression and activity in cancer: implications for use in patients with solid tumors.
J Natl Cancer Inst,
June 21, 2006;
98(12):
812 - 824.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Bernard-Pierrot, A. Brams, C. Dunois-Larde, A. Caillault, S. G. Diez de Medina, D. Cappellen, G. Graff, J. P. Thiery, D. Chopin, D. Ricol, et al.
Oncogenic properties of the mutated forms of fibroblast growth factor receptor 3b
Carcinogenesis,
April 1, 2006;
27(4):
740 - 747.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Agnelli, S. Bicciato, M. Mattioli, S. Fabris, D. Intini, D. Verdelli, L. Baldini, F. Morabito, V. Callea, L. Lombardi, et al.
Molecular Classification of Multiple Myeloma: A Distinct Transcriptional Profile Characterizes Patients Expressing CCND1 and Negative for 14q32 Translocations
J. Clin. Oncol.,
October 10, 2005;
23(29):
7296 - 7306.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Logie, C. Dunois-Larde, C. Rosty, O. Levrel, M. Blanche, A. Ribeiro, J.-M. Gasc, J. Jorcano, S. Werner, X. Sastre-Garau, et al.
Activating mutations of the tyrosine kinase receptor FGFR3 are associated with benign skin tumors in mice and humans
Hum. Mol. Genet.,
May 1, 2005;
14(9):
1153 - 1160.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Dring, F. E. Davies, J. A. L. Fenton, P. L. Roddam, K. Scott, D. Gonzalez, S. Rollinson, A. C. Rawstron, K. S. Rees-Unwin, C. Li, et al.
A Global Expression-based Analysis of the Consequences of the t(4;14) Translocation in Myeloma
Clin. Cancer Res.,
September 1, 2004;
10(17):
5692 - 5701.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. N. Meyer, R. F. Gastwirt, D. D. Schlaepfer, and D. J. Donoghue
The Cytoplasmic Tyrosine Kinase Pyk2 as a Novel Effector of Fibroblast Growth Factor Receptor 3 Activation
J. Biol. Chem.,
July 2, 2004;
279(27):
28450 - 28457.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Fonseca, B. Barlogie, R. Bataille, C. Bastard, P. L. Bergsagel, M. Chesi, F. E. Davies, J. Drach, P. R. Greipp, I. R. Kirsch, et al.
Genetics and Cytogenetics of Multiple Myeloma: A Workshop Report
Cancer Res.,
February 15, 2004;
64(4):
1546 - 1558.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Soverini, M. Cavo, C. Cellini, C. Terragna, E. Zamagni, D. Ruggeri, N. Testoni, P. Tosi, A. de Vivo, M. Amabile, et al.
Cyclin D1 overexpression is a favorable prognostic variable for newly diagnosed multiple myeloma patients treated with high-dose chemotherapy and single or double autologous transplantation
Blood,
September 1, 2003;
102(5):
1588 - 1594.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. N. Onwuazor, X.-Y. Wen, D.-Y. Wang, L. Zhuang, E. Masih-Khan, J. Claudio, B. Barlogie, J. D. Shaughnessy Jr, and A. K. Stewart
Mutation, SNP, and isoform analysis of fibroblast growth factor receptor 3 (FGFR3) in 150 newly diagnosed multiple myeloma patients
Blood,
July 15, 2003;
102(2):
772 - 773.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. J. Keats, T. Reiman, C. A. Maxwell, B. J. Taylor, L. M. Larratt, M. J. Mant, A. R. Belch, and L. M. Pilarski
In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression
Blood,
February 15, 2003;
101(4):
1520 - 1529.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. B. Pollett, S. Trudel, D. Stern, Z. H. Li, and A. K. Stewart
Overexpression of the myeloma-associated oncogene fibroblast growth factor receptor 3 confers dexamethasone resistance
Blood,
November 15, 2002;
100(10):
3819 - 3821.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Kong, C. S. Wang, and D. J. Donoghue
Interaction of Fibroblast Growth Factor Receptor 3 and the Adapter Protein SH2-B. A ROLE IN STAT5 ACTIVATION
J. Biol. Chem.,
May 3, 2002;
277(18):
15962 - 15970.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Guasch, V. Ollendorff, J.-P. Borg, D. Birnbaum, and M.-J. Pebusque
8p12 Stem Cell Myeloproliferative Disorder: the FOP-Fibroblast Growth Factor Receptor 1 Fusion Protein of the t(6;8) Translocation Induces Cell Survival Mediated by Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase/Akt/mTOR Pathways
Mol. Cell. Biol.,
December 1, 2001;
21(23):
8129 - 8142.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Reiman, K. Seeberger, B. J. Taylor, A. J. Szczepek, J. Hanson, M. J. Mant, R. W. Coupland, A. R. Belch, and L. M. Pilarski
Persistent preswitch clonotypic myeloma cells correlate with decreased survival: evidence for isotype switching within the myeloma clone
Blood,
November 1, 2001;
98(9):
2791 - 2799.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Q. Wang, R. P. Green, G. Zhao, and D. M. Ornitz
Differential regulation of endochondral bone growth and joint development by FGFR1 and FGFR3 tyrosine kinase domains
Development,
October 1, 2001;
128(19):
3867 - 3876.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Billerey, D. Chopin, M.-H. Aubriot-Lorton, D. Ricol, S. Gil Diez de Medina, B. Van Rhijn, M.-P. Bralet, M.-A. Lefrere-Belda, J.-B. Lahaye, C. C. Abbou, et al.
Frequent FGFR3 Mutations in Papillary Non-Invasive Bladder (pTa) Tumors
Am. J. Pathol.,
June 1, 2001;
158(6):
1955 - 1959.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Perfetti, A. M. L. Coluccia, D. Intini, U. Malgeri, M. C. Vignarelli, S. Casarini, G. Merlini, and A. Neri
Translocation t(4;14)(p16.3;q32) Is a Recurrent Genetic Lesion in Primary Amyloidosis
Am. J. Pathol.,
May 1, 2001;
158(5):
1599 - 1603.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. Li, Y. X. Zhu, E. E. Plowright, P. L. Bergsagel, M. Chesi, B. Patterson, T. S. Hawley, R. G. Hawley, and A. K. Stewart
The myeloma-associated oncogene fibroblast growth factor receptor 3 is transforming in hematopoietic cells
Blood,
April 15, 2001;
97(8):
2413 - 2419.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. C. Hart, S. C. Robertson, and D. J. Donoghue
Identification of Tyrosine Residues in Constitutively Activated Fibroblast Growth Factor Receptor 3 Involved in Mitogenesis, Stat Activation, and Phosphatidylinositol 3-Kinase Activation
Mol. Biol. Cell,
April 1, 2001;
12(4):
931 - 942.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
P. J. Ho, R. D. Brown, G. J. Pelka, A. Basten, J. Gibson, and D. E. Joshua
Illegitimate switch recombinations are present in approximately half of primary myeloma tumors, but do not relate to known prognostic indicators or survival
Blood,
January 15, 2001;
97(2):
490 - 495.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
U. Malgeri, L. Baldini, V. Perfetti, S. Fabris, M. C. Vignarelli, G. Colombo, V. Lotti, S. Compasso, S. Bogni, L. Lombardi, et al.
Detection of t(4;14)(p16.3;q32) Chromosomal Translocation in Multiple Myeloma by Reverse Transcription-Polymerase Chain Reaction Analysis of IGH-MMSET Fusion Transcripts
Cancer Res.,
August 1, 2000;
60(15):
4058 - 4061.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
T. G. Willis and M. J. S. Dyer
The role of immunoglobulin translocations in the pathogenesis of B-cell malignancies
Blood,
August 1, 2000;
96(3):
808 - 822.
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Szczepanski, M. B. van 't Veer, I. L. M. Wolvers-Tettero, A. W. Langerak, and J. J. M. van Dongen
Molecular features responsible for the absence of immunoglobulin heavy chain protein synthesis in an IgH- subgroup of multiple myeloma
Blood,
August 1, 2000;
96(3):
1087 - 1093.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Pruneri, S. Fabris, L. Baldini, N. Carboni, S. Zagano, M. A. Colombi, G. Ciceri, L. Lombardi, M. Rocchi, R. Buffa, et al.
Immunohistochemical Analysis of Cyclin D1 Shows Deregulated Expression in Multiple Myeloma with the t(11;14)
Am. J. Pathol.,
May 1, 2000;
156(5):
1505 - 1513.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. W. G. Janssen, J.-W. Vaandrager, T. Heuser, A. Jauch, P. M. Kluin, E. Geelen, P. L. Bergsagel, W. M. Kuehl, H. G. Drexler, T. Otsuki, et al.
Concurrent activation of a novel putative transforming gene, myeov, and cyclin D1 in a subset of multiple myeloma cell lines with t(11;14)(q13;q32)
Blood,
April 15, 2000;
95(8):
2691 - 2698.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Macintyre, D. Willerford, and S. W. Morris
Non-Hodgkin's Lymphoma: Molecular Features of B Cell Lymphoma
Hematology,
January 1, 2000;
2000(1):
180 - 204.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Avet-Loiseau, J.-Y. Li, N. Morineau, T. Facon, C. Brigaudeau, J.-L. Harousseau, B. Grosbois, and R. Bataille
Monosomy 13 Is Associated With the Transition of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma
Blood,
October 15, 1999;
94(8):
2583 - 2589.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Finelli, S. Fabris, S. Zagano, L. Baldini, D. Intini, L. Nobili, L. Lombardi, A. T. Maiolo, and A. Neri
Detection of t(4;14)(p16.3;q32) Chromosomal Translocation in Multiple Myeloma by Double-Color Fluorescent In Situ Hybridization
Blood,
July 15, 1999;
94(2):
724 - 732.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Ronchetti, P. Finelli, R. Richelda, L. Baldini, M. Rocchi, L. Viggiano, A. Cuneo, S. Bogni, S. Fabris, L. Lombardi, et al.
Molecular Analysis of 11q13 Breakpoints in Multiple Myeloma
Blood,
February 15, 1999;
93(4):
1330 - 1337.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D.-Y. Choi, J.-J. Toledo-Aral, H. Y. Lin, I. Ischenko, L. Medina, P. Safo, G. Mandel, S. R. Levinson, S. Halegoua, and M. J. Hayman
Fibroblast Growth Factor Receptor 3 Induces Gene Expression Primarily through Ras-independent Signal Transduction Pathways
J. Biol. Chem.,
February 9, 2001;
276(7):
5116 - 5122.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
