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Detection of MUM1/IRF4-IgH fusion in multiple myeloma
S Yoshida1, N Nakazawa, S Iida
1Second Department of Internal Medicine, Nagoya City University Medical School, Nagoya, Japan.
Abstract:
MUM1 (multiple myeloma oncogene 1)/IRF4 (interferon regulatory factor 4) gene has been identified as an oncogene transcriptionally activated by t(6;14)(p25;q32) chromosomal translocation in multiple myeloma (MM). The significance of this alteration in MM remains unknown, as it is not detectable by means of conventional cytogenetic analysis. To address this issue, we established diagnostic procedures based on pulsed-field gel electrophoresis (PFGE) analysis and double color fluorescence in situ hybridization (DCFISH) using DNA probes derived from the MUM1 and the immunoglobulin heavy chain (IgH) gene loci. Among a panel of 17 MM cell lines, three (17.6%) showed fusions between these two loci, which resulted in the juxtaposition of the MUM1 to the IgH 3' alpha-enhancer region by virtue of t(6;14) or insertion of the IgH sequences into the vicinity of the MUM1 gene and in the concomitant overexpression of the MUM1 mRNA. With similar results, fusions between MUM1 and IgH loci were observed by means of interphase DCFISH in eight (21.1%) out of the 38 MM cases, although no definite relationships between MUM1 status and specific clinical findings could be established.
Insights
The MUM1/IRF4 oncogene is activated by a t(6;14) translocation in multiple myeloma (MM). New diagnostic methods detect this fusion, revealing its presence in over 20% of MM cases.
Area of Science:
- Genetics
- Molecular Biology
- Oncology
Background:
- The MUM1/IRF4 gene is an oncogene in multiple myeloma (MM), transcriptionally activated by the t(6;14) chromosomal translocation.
- The clinical significance of this specific genetic alteration in MM is not well understood, as it is missed by conventional cytogenetic analyses.
Purpose of the Study:
- To develop and apply novel diagnostic methods for detecting the t(6;14) translocation involving the MUM1/IRF4 gene in multiple myeloma.
- To investigate the frequency of MUM1/IRF4 gene alterations in MM cell lines and patient samples.
Main Methods:
- Development of diagnostic procedures using pulsed-field gel electrophoresis (PFGE) and double color fluorescence in situ hybridization (DCFISH).
- Utilized DNA probes targeting the MUM1 and immunoglobulin heavy chain (IgH) gene loci to detect translocations and fusions.
- Analyzed 17 MM cell lines and 38 MM patient samples.
Main Results:
- Fusions between the MUM1 and IgH loci, indicative of the t(6;14) translocation or IgH insertion near MUM1, were identified in 17.6% of MM cell lines.
- Interphase DCFISH detected MUM1-IgH fusions in 21.1% of the 38 MM cases studied.
- Detected MUM1 gene overexpression correlating with these genetic alterations.
Conclusions:
- The MUM1/IRF4 gene rearrangement due to t(6;14) or related events occurs in a significant subset of multiple myeloma.
- Established PFGE and DCFISH are effective tools for diagnosing this specific genetic alteration in MM.
- No clear correlation was found between MUM1 status and specific clinical features in this cohort.