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Translocation T(4;14)(p16.3;q32) is a recurrent genetic lesion in primary amyloidosis
V Perfetti1, A M Coluccia, D Intini
1Department of Internal Medicine, Internal Medicine and Medical Oncology, University of Pavia, Pavia, Italy.
Abstract:
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.
Insights
The t(4;14) translocation, previously found in multiple myeloma, is also present in primary amyloidosis patients. This genetic abnormality leads to altered MMSET gene expression, offering new insights into amyloidosis pathobiology.
Area of Science:
- Hematology
- Genetics
- Oncology
Background:
- Primary amyloidosis involves light chain deposition and is often fatal.
- The molecular basis of amyloidosis remains largely unknown.
- A t(4;14) translocation deregulates FGFR3 and MMSET genes in multiple myeloma.
Purpose of the Study:
- To investigate the prevalence of the t(4;14) translocation in primary amyloidosis.
- To identify IGH/MMSET hybrid transcripts in AL patients.
Main Methods:
- Reverse transcriptase-polymerase chain reaction (RT-PCR) was used.
- The study analyzed 42 patients with primary amyloidosis (AL).
- Detection of IGH/MMSET chimeric transcripts was performed.
Main Results:
- The t(4;14) translocation was detected in 14% (6 of 42) of AL patients.
- Chimeric transcripts involved breakpoints in intron 3 or alternative splicing.
- All fusion transcripts excluded the first translated MMSET exon, suggesting truncated protein production.
Conclusions:
- The t(4;14)(p16.3;q32) translocation is a recurrent genetic finding in primary amyloidosis.
- This translocation may contribute to the molecular pathobiology of AL.
- Further research into the role of MMSET deregulation in amyloidosis is warranted.