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A global expression-based analysis of the consequences of the t(4;14) translocation in myeloma
Ann M Dring1, Faith E Davies, James A L Fenton
1Academic Unit of Haematology and Oncology, University of Leeds, Leeds, United Kingdom.
Purpose:
Our purpose in this report was to define genes and pathways dysregulated as a consequence of the t(4;14) in myeloma, and to gain insight into the downstream functional effects that may explain the different prognosis of this subgroup.
Experimental Design:
Fibroblast growth factor receptor 3 (FGFR3) overexpression, the presence of immunoglobulin heavy chain-multiple myeloma SET domain (IgH-MMSET) fusion products and the identification of t(4;14) breakpoints were determined in a series of myeloma cases. Differentially expressed genes were identified between cases with (n = 5) and without (n = 24) a t(4;14) by using global gene expression analysis.
Results:
Cases with a t(4;14) have a distinct expression pattern compared with other cases of myeloma. A total of 127 genes were identified as being differentially expressed including MMSET and cyclin D2, which have been previously reported as being associated with this translocation. Other important functional classes of genes include cell signaling, apoptosis and related genes, oncogenes, chromatin structure, and DNA repair genes. Interestingly, 25% of myeloma cases lacking evidence of this translocation had up-regulation of the MMSET transcript to the same level as cases with a translocation.
Conclusions:
t(4;14) cases form a distinct subgroup of myeloma cases with a unique gene signature that may account for their poor prognosis. A number of non-t(4;14) cases also express MMSET consistent with this gene playing a role in myeloma pathogenesis.
Insights
The t(4;14) translocation creates a distinct myeloma subgroup with a unique gene signature, potentially explaining their poor prognosis. MMSET gene expression also occurs in some non-t(4;14) myeloma cases.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Multiple myeloma is a plasma cell malignancy.
- The t(4;14) chromosomal translocation is a recurrent abnormality in multiple myeloma.
- This translocation is associated with a distinct clinical and biological subgroup.
Purpose of the Study:
- To identify genes and pathways dysregulated by the t(4;14) translocation in myeloma.
- To understand the downstream functional consequences of t(4;14) that may explain the subgroup's prognosis.
- To investigate the role of MMSET in myeloma pathogenesis.
Main Methods:
- Myeloma cases were analyzed for t(4;14) breakpoints, FGFR3 overexpression, and IgH-MMSET fusion products.
- Global gene expression analysis was performed to compare cases with and without t(4;14).
- Differentially expressed genes were identified using statistical methods.
Main Results:
- Cases with t(4;14) exhibited a distinct gene expression profile compared to other myeloma cases.
- 127 differentially expressed genes were identified, including MMSET and cyclin D2.
- Genes involved in cell signaling, apoptosis, oncogenesis, chromatin structure, and DNA repair were significantly altered.
- A notable finding was the MMSET transcript up-regulation in 25% of non-t(4;14) myeloma cases.
Conclusions:
- Myeloma cases with t(4;14) represent a distinct subgroup characterized by a unique gene signature, potentially contributing to their poor prognosis.
- The study suggests that MMSET plays a role in myeloma pathogenesis, as evidenced by its expression in both t(4;14) and some non-t(4;14) cases.
