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, Antonino Neri

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Abstract

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, α, and γ regions to detect cases bearing IGH switch-mediated chromosomal translocations. We evaluated DNA of 88 non-karyotyped 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.

Original languageEnglish
Pages (from-to)4062-4070
Number of pages9
JournalBlood
Volume90
Issue number10
Publication statusPublished - Nov 15 1997

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Receptor, Fibroblast Growth Factor, Type 3
Genetic Translocation
Immunoglobulin Heavy Chains
Multiple Myeloma
Genes
Chromosomes
Cells
Plasma Cell Leukemia
Tumors
Bearings (structural)
Switches
Plasmas
Southern Blotting
Fluorescence In Situ Hybridization
Cell Line
Joining
Substitution reactions
Neoplasms
Chemical activation
Amino Acid Substitution

ASJC Scopus subject areas

  • Hematology

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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. / Richelda, Raffaella; Ronchetti, Domenica; Baldini, Luca; Cro, Lilla; Viggiano, Luigi; Marzella, Rosalia; Rocchi, Mariano; Otsuki, Takemi; Lombardi, Luigia; Maiolo, Anna Teresa; Neri, Antonino.

In: Blood, Vol. 90, No. 10, 15.11.1997, p. 4062-4070.

Research output: Contribution to journalArticle

Richelda, R, Ronchetti, D, Baldini, L, Cro, L, Viggiano, L, Marzella, R, Rocchi, M, Otsuki, T, Lombardi, L, Maiolo, AT & Neri, A 1997, 'A novel chromosomal translocation t(4; 14)(p16.3;q32) in multiple myeloma involves the fibroblast growth-factor receptor 3 gene', Blood, vol. 90, no. 10, pp. 4062-4070.
Richelda, Raffaella ; Ronchetti, Domenica ; Baldini, Luca ; Cro, Lilla ; Viggiano, Luigi ; Marzella, Rosalia ; Rocchi, Mariano ; Otsuki, Takemi ; Lombardi, Luigia ; Maiolo, Anna Teresa ; Neri, Antonino. / A novel chromosomal translocation t(4; 14)(p16.3;q32) in multiple myeloma involves the fibroblast growth-factor receptor 3 gene. In: Blood. 1997 ; Vol. 90, No. 10. pp. 4062-4070.
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abstract = "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, α, and γ regions to detect cases bearing IGH switch-mediated chromosomal translocations. We evaluated DNA of 88 non-karyotyped 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.",
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T1 - A novel chromosomal translocation t(4; 14)(p16.3;q32) in multiple myeloma involves the fibroblast growth-factor receptor 3 gene

AU - Richelda, Raffaella

AU - Ronchetti, Domenica

AU - Baldini, Luca

AU - Cro, Lilla

AU - Viggiano, Luigi

AU - Marzella, Rosalia

AU - Rocchi, Mariano

AU - Otsuki, Takemi

AU - Lombardi, Luigia

AU - Maiolo, Anna Teresa

AU - Neri, Antonino

PY - 1997/11/15

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N2 - 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, α, and γ regions to detect cases bearing IGH switch-mediated chromosomal translocations. We evaluated DNA of 88 non-karyotyped 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.

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