A global expression-based analysis of the consequences of the t(4;14) translocation in myeloma
ABSTRACT 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.
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.
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.
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.
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ABSTRACT: To investigate the patterns of genetic lesions in a panel of 23 human multiple myeloma cell lines (HMCLs), we made a genomic integrative analysis involving FISH, and both gene expression and genome-wide profiling approaches. The expression profiles of the genes targeted by the main IGH translocations showed that the WHSC1/MMSET gene involved in t(4;14)(p16;q32) was expressed at different levels in all of the HMCLs, and that the expression of the MAF gene was not restricted to the HMCLs carrying t(14;16)(q32;q23). Supervised analyses identified a limited number of genes specifically associated with t(4;14) and involved in different biological processes. The signature related to MAF/MAFB expression included the known MAF target genes CCND2 and ITGB7, as well as genes controlling cell shape and cell adhesion. Genome-wide DNA profiling allowed the identification of a gain on chromosome arm 1q in 88% of the analyzed cell lines, together with recurrent gains on 8q, 18q, 7q, and 20q; the most frequent deletions affected 1p, 13q, 17p, and 14q; and almost all of the cell lines presented LOH on chromosome 13. Two hundred and twenty-two genes were found to be simultaneously overexpressed and amplified in our panel, including the BCL2 locus at 18q21.33. Our data further support the evidence of the genomic complexity of multiple myeloma and reinforce the role of an integrated genomic approach in improving our understanding of the molecular pathogenesis of the disease. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.Genes Chromosomes and Cancer 03/2007; 46(3):226-38. DOI:10.1002/gcc.20404 · 3.84 Impact Factor
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ABSTRACT: Standard fluorescence in situ hybridization (FISH) easily detects nonrandom karyotypic abnormalities in multiple myeloma (MM) at disease presentation, when tumor burden is high. In contrast, the detection of residual MM using the standard 200 unselected nonmitotic nuclei FISH approach correlates poorly with residual disease detected by morphology, flow cytometry, immunohistochemistry, or reverse-transcription polymerase chain reaction (RT-PCR). We have used sequential May-Grunwald Giemsa stain to identify plasma cell populations, followed by FISH analyses (target FISH or T-FISH) to detect immunoglobulin heavy-chain gene (IGH) rearrangements, 13q or 17p deletions, or hyperdiploidy. In this study, 115 samples were collected from 100 patients with MM regardless of treatment status. In this proof-of-principle prospective study, T-FISH detected MM in 52 samples (45%), a percentage similar to that obtained by pathology. Disease detection increased from 5.6% with standard FISH to 48% with T-FISH, and cell culture experiments showed that T-FISH consistently detected a clonal abnormality at dilutions of 10(-3). In five patients, T-FISH further identified myelodysplastic-associated karyotypic changes restricted to myeloid cells. Our observations suggest that T-FISH identifies cell lineage involvement of cytogenetic abnormalities, improves detection of low-level or residual MM, and may define the coexistence of hematologic karyotypic changes in individual patients.Cancer Genetics and Cytogenetics 05/2005; 158(2):99-109. DOI:10.1016/j.cancergencyto.2005.01.006 · 1.93 Impact Factor