Article

Molecular Dissection of Hyperdiploid Multiple Myeloma by Gene Expression Profiling

Department of Hematology-Oncology, Mayo Clinic, Scottsdale, Arizona, USA.
Cancer Research (Impact Factor: 9.28). 04/2007; 67(7):2982-9. DOI: 10.1158/0008-5472.CAN-06-4046
Source: PubMed

ABSTRACT Hyperdiploid multiple myeloma (H-MM) is the most common form of myeloma. In this gene expression profiling study, we show that H-MM is defined by a protein biosynthesis signature that is primarily driven by a gene dosage mechanism as a result of trisomic chromosomes. Within H-MM, four independently validated patient clusters overexpressing nonoverlapping sets of genes that form cognate pathways/networks that have potential biological importance in multiple myeloma were identified. One prominent cluster, cluster 1, is characterized by high expression of cancer testis antigen and proliferation-associated genes. Tumors from these patients were more proliferative than tumors in other clusters (median plasma cell labeling index, 3.8; P < 0.05). Another cluster, cluster 3, is characterized by genes involved in tumor necrosis factor/nuclear factor-kappaB signaling and antiapoptosis. These patients have better response to bortezomib as compared with patients within other clusters (70% versus 29%; P = 0.02). Furthermore, for a group of patients generally thought to have better prognosis, a cluster of patients with short survival (cluster 1; median survival, 27 months) could be identified. This analysis illustrates the heterogeneity within H-MM and the importance of defining specific cytogenetic prognostic factors. Furthermore, the signatures that defined these clusters may provide a basis for tailoring treatment to individual patients.

Download full-text

Full-text

Available from: Seungchan Kim, Jul 28, 2015
0 Followers
 · 
138 Views
  • Source
    • "This however is unlikely, as myeloma has a distinctively low proliferation rate. Instead, it is proposed that the overexpression is driven by gene copy number increases, with hyperdiploid cells then possessing more ribosomes and translational initiation factors to promote myelomagenesis through the overexpression of cellular growth genes [54] "
    [Show abstract] [Hide abstract]
    ABSTRACT: Multiple myeloma is a malignant proliferation of monoclonal plasma cells leading to clinical features that include hypercalcaemia, renal dysfunction, anaemia, and bone disease (frequently referred to by the acronym CRAB) which represent evidence of end organ failure. Recent evidence has revealed myeloma to be a highly heterogeneous disease composed of multiple molecularly-defined subtypes each with varying clinicopathological features and disease outcomes. The major division within myeloma is between hyperdiploid and nonhyperdiploid subtypes. In this division, hyperdiploid myeloma is characterised by trisomies of certain odd numbered chromosomes, namely, 3, 5, 7, 9, 11, 15, 19, and 21 whereas nonhyperdiploid myeloma is characterised by translocations of the immunoglobulin heavy chain alleles at chromosome 14q32 with various partner chromosomes, the most important of which being 4, 6, 11, 16, and 20. Hyperdiploid and nonhyperdiploid changes appear to represent early or even initiating mutagenic events that are subsequently followed by secondary aberrations including copy number abnormalities, additional translocations, mutations, and epigenetic modifications which lead to plasma cell immortalisation and disease progression. The following review provides a comprehensive coverage of the genetic and epigenetic events contributing to the initiation and progression of multiple myeloma and where possible these abnormalities have been linked to disease prognosis.
    Advances in Hematology 04/2014; 2014:864058. DOI:10.1155/2014/864058
  • Source
    • "The expression levels of the 308 differentially expressed genes discriminating CMA-03/06 versus CMA-03 cell lines were evaluated in a dataset of 274 samples including 18 normal PCs, 28 monoclonal gammopathy of undetermined significance (MGUS), 19 smoldering MM (sMM), 200 newly diagnosed MM, and nine plasma cell leukemia (PCL) patients from three independent cohorts (GSE13591 (Agnelli et al., 2009), GSE6477 (Chng et al., 2007), GSE6691 (Gutierrez et al., 2007)), profiled on GeneChip HG-U133A arrays and annotated using GeneAnnot custom chip definition file (GA v. 2.2.0) (Todoerti et al., 2013). As previously described by Todoerti et al. (2013), the Kruskal–Wallis and the Jonckheere–Terpstra tests were applied to the selected gene list to identify significant differential expressions and trends from healthy donors through PCL cases. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We explored the molecular mechanisms involved in the establishement of CMA-03/06, an IL-6-independent variant of the multiple myeloma cell line CMA-03 previously generated in our Institution. CMA-03/06 cells grow in the absence of IL-6 with a doubling time comparable with that of CMA-03 cells; neither the addition of IL6 (IL-6) to the culture medium nor co-culture with multipotent mesenchymal stromal cells increases the proliferation rate, although they maintain the responsiveness to IL-6 stimulation as demonstrated by STAT1, STAT3, and STAT5 induction. IL-6 independence of CMA-03/06 cells is not apparently due to the development of an autocrine IL-6 loop, nor to the observed moderate constitutive activation of STAT5 and STAT3, since STAT3 silencing does not affect cell viability or proliferation. When compared to the parental cell line, CMA-03/06 cells showed an activated pattern of the NF-κB pathway. This finding is supported by gene expression profiling (GEP) analysis identifying an appreciable fraction of modulated genes (28/308) in the CMA-03/06 subclone reported to be involved in this pathway. Furthermore, although more resistant to apoptotic stimuli compared to the parental cell line, CMA-03/06 cells display a higher sensibility to NF-κB inhibition induced by bortezomib. Finally, GEP analysis suggests an involvement of a number of cytokines, which might contribute to IL-6 independence of CMA-03/06 by stimulating growth and antiapoptotic processes. In conclusion, the parental cell-line CMA-03 and its variant CMA-03/06 represent a suitable model to further investigate molecular mechanisms involved in the IL-6-independent growth of myeloma cells. © 2013 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 02/2014; 53(2):154-67. DOI:10.1002/gcc.22127 · 3.84 Impact Factor
  • Source
    • "Among patients with H-MM, 13 deletion and chromosome 1 abnormalities have not apparent prognostic significance but the presence of deletions of 17p13 in remains an important prognostic factor. In addition, a study showed that most of the prognostic value of H-MM was related to the gain of chromosome 5 [24] [26]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: While no specific genetic markers are required in the diagnosis of multiple myeloma (MM), multiple genetic abnormalities and gene signatures are used in disease prognostication and risk stratification. This is particularly important for the adequate identification of the high-risk MM group, which does not benefit from any of the current therapies, and novel approaches need to be proposed. Fluorescence in situ hybridization (FISH) has been employed for establishing risk-based stratification and still remains the most used genetic technique in the clinical routine. The incorporation of gene expression profiling (GEP) in the study of MM has shown to be a very powerful test in the patient stratification, but its incorporation in clinical routine depends on some technical and logistic resolutions. Thus, FISH still remains the gold standard test for detecting genomic abnormalities and outcome discrimination in MM.
    09/2011; 2011:798089. DOI:10.4061/2011/798089
Show more