Translocation T(4;14)(p16.3;q32) is a recurrent genetic lesion in primary amyloidosis.

Primary amyloidosis is a fatal disorder characterized by low numbers of clonal plasma cells in the bone marrow and the systemic deposition of light chain fragments in the form of amyloid. The molecular pathobiology of amyloidosis is primarily unknown. Recently, a novel karyotypically undetectable t(4;14)(p16.3;q32) translocation has been identified in approximately 20% of multiple myeloma patients. The translocation leads to the apparent deregulation of two genes located on 4p16.3, the fibroblast growth-factor receptor 3 (FGFR3), and the putative transcription factor multiple myeloma SET domain (MMSET), and to the generation of IGH/MMSET hybrid transcripts. In this study, we investigated the presence of the t(4;14) translocation in 42 AL patients using a reverse transcriptase-polymerase chain reaction assay for the detection of IGH/MMSET transcripts. Chimeric transcripts were found in six patients (14%) and were consistent with a 4p16.3 breakpoint involving intron 3 and juxtaposing IGH regions to exon 4. In three of these cases, hybrid transcripts juxtaposing IGH regions to exon 5 were also observed and were probably the result of an alternative splicing skipping exon 4. Because all of the fusion transcripts (six of six) excluded exon 3, the first translated MMSET exon, only putative 5' truncated MMSET proteins could be generated. In conclusion, our results demonstrate that the t(4;14)(p16.3;q32) translocation is a recurrent genetic lesion in primary amyloidosis.

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.

We and others have recently identified a novel recurring t(4;14)(p16.3; q32) translocation in multiple myeloma (MM) that leads to an apparent deregulation of the FGFR3 and WHSC1/MMSET genes. Because the presence of IGH-MMSET hybrid transcripts has been found in MM cell lines with t(4;14), they may represent a specific tumor-associated marker in MM. In this study, we developed a reverse transcription-PCR (RTPCR) assay for detecting chimeric transcripts from all of the 4p16.3 breakpoints identified thus far, and we used it to investigate a representative panel of 53 MM patients and 16 patients with monoclonal gammopathy of uncertain significance; in addition, t(4;14) was investigated in all of the MM patients by means of two-color fluorescence in situ hybridization. IGH-MMSET transcripts were found in 11 of the 53 (20%) MM cases and 1 of 16 (6%) cases of monoclonal gammopathy of uncertain significance. There was complete concordance between the RT-PCR and fluorescence in situ hybridization analyses of the MM cases. The results of this study indicate that RT-PCR is a sensitive and reliable method of detecting t(4;14) and suggest that it may be useful for monitoring the disease in a significant proportion of patients.