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

Marta Chesi, E. Nardini, L. A. Brents, E. Schrock, T. Ried, W. M. Kuehl, Peter Leif Bergsagel

Research output: Contribution to journalArticle

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Abstract

Dysregulation of oncogenes by translocation to the IgH locus (14q32) is a seminal event in the pathogenesis of B-cell tumours. In multiple myeloma (MM), translocations 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 tumour, 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 fibroblast 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.

Original languageEnglish (US)
Pages (from-to)260-264
Number of pages5
JournalNature Genetics
Volume16
Issue number3
DOIs
StatePublished - 1997
Externally publishedYes

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Receptor, Fibroblast Growth Factor, Type 3
Multiple Myeloma
Mutation
Neoplasms
Oncogenes
Thanatophoric Dysplasia
Chromosomes
Chromosome Breakpoints
Chromosomes, Human, Pair 4
Cyclin D1
Southern Blotting
Tumor Cell Line
Genes
B-Lymphocytes
Alleles
Ligands
Incidence
Proteins

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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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. / Chesi, Marta; Nardini, E.; Brents, L. A.; Schrock, E.; Ried, T.; Kuehl, W. M.; Bergsagel, Peter Leif.

In: Nature Genetics, Vol. 16, No. 3, 1997, p. 260-264.

Research output: Contribution to journalArticle

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abstract = "Dysregulation of oncogenes by translocation to the IgH locus (14q32) is a seminal event in the pathogenesis of B-cell tumours. In multiple myeloma (MM), translocations 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 tumour, 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 fibroblast 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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AU - Brents, L. A.

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AU - Ried, T.

AU - Kuehl, W. M.

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