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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple myeloma (MM) is the most common form of plasma cell dyscrasia, characterized by a marked heterogeneity of genetic lesions and clinical course. It may develop from a premalignant condition (monoclonal gammopathy of undetermined significance, MGUS) or progress from intramedullary to extramedullary forms (plasma cell leukemia, PCL). To provide insights into the molecular characterization of plasma cell dyscrasias and to investigate the contribution of specific genetic lesions to the biological and clinical heterogeneity of MM, we analysed the gene expression profiles of plasma cells isolated from seven MGUS, 39 MM and six PCL patients by means of DNA microarrays. MMs resulted highly heterogeneous at transcriptional level, whereas the differential expression of genes mainly involved in DNA metabolism and proliferation distinguished MGUS from PCLs and the majority of MM cases. The clustering of MM patients was mainly driven by the presence of the most recurrent translocations involving the immunoglobulin heavy-chain locus. Distinct gene expression patterns have been found to be associated with different lesions: the overexpression of CCND2 and genes involved in cell adhesion pathways was observed in cases with deregulated MAF and MAFB, whereas genes upregulated in cases with the t(4;14) showed apoptosis-related functions. The peculiar finding in patients with the t(11;14) was the downregulation of the alpha-subunit of the IL-6 receptor. In addition, we identified a set of cancer germline antigens specifically expressed in a subgroup of MM patients characterized by an aggressive clinical evolution, a finding that could have implications for patient classification and immunotherapy.
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PMID:Gene expression profiling of plasma cell dyscrasias reveals molecular patterns associated with distinct IGH translocations in multiple myeloma. 1573 37

Two oncogenic pathways have been hypothesized for multiple myeloma (MM) and premalignant monoclonal gammopathy of undetermined significance (MGUS) tumors: a nonhyperdiploid pathway associated with a high prevalence of IgH translocations and a hyperdiploid pathway associated with multiple trisomies of 8 chromosomes. Cyclin D1, D2, or D3 expression appears to be increased and/or dysregulated in virtually all MM tumors despite their low proliferative capacity. Translocations can directly dysregulate CCND1 (11q13) or CCND3 (6p21), or MAF (16q23) or MAFB (20q11) transcription factors that target CCND2. Biallelic dysregulation of CCND1 occurs in nearly 40% of tumors, most of which are hyperdiploid. Other tumors express increased CCND2, either with or without a t(4;14) translocation. Using gene expression profiling to identify 5 recurrent translocations, specific trisomies, and expression of cyclin D genes, MM tumors can be divided into 8 TC (translocation/cyclin D) groups (11q13, 6p21, 4p16, maf, D1, D1+D2, D2, and none) that appear to be defined by early, and perhaps initiating, oncogenic events. However, despite subsequent progression events, these groups have differing gene expression profiles and also significant differences in the prevalence of bone disease, frequency at relapse, and progression to extramedullary tumor.
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PMID:Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. 1575 96

Multiple myeloma is a tumor of somatically mutated, isotype-switched plasma cells that accumulate in the bone marrow leading to bone destruction and bone marrow failure. The germinal center processes of somatic hypermutation and switch recombination are implicated in the development of recurrent immunoglobulin gene translocations in 40% of patients. These affect five loci: 11q13, 6p21, 4p16, 16q23 and 20q11, leading to dysregulation of CCND1, CCND2, FGFR3/MMSET, c-MAF and MAFB respectively. The remaining 60% of patients can be divided into four groups based on their expression of CCND1 and CCND2. The largest group (40%) ectopically express CCND1 bi-allelically and have hyperdiploidy with multiple trisomies of chromosomes 3, 5, 7, 9, 11, 15, 19 and 21. The translocation and cyclin D (TC) groups identify patients with different genetics, biology, clinical features, prognosis and response to therapy.
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PMID:Early genetic events provide the basis for a clinical classification of multiple myeloma. 1630 2

We previously developed a multivariate model based on the RNA expression of 6 genes (LMO2, BCL6, FN1, CCND2, SCYA3, and BCL2) that predicts survival in diffuse large B-cell lymphoma (DLBCL) patients. Since LMO2 emerged as the strongest predictor of superior outcome, we generated a monoclonal anti-LMO2 antibody in order to study its tissue expression pattern. Immunohistologic analysis of over 1200 normal and neoplastic tissue and cell lines showed that LMO2 protein is expressed as a nuclear marker in normal germinal-center (GC) B cells and GC-derived B-cell lines and in a subset of GC-derived B-cell lymphomas. LMO2 was also expressed in erythroid and myeloid precursors and in megakaryocytes and also in lymphoblastic and acute myeloid leukemias. It was rarely expressed in mature T, natural killer (NK), and plasma cell neoplasms and was absent from nonhematolymphoid tissues except for endothelial cells. Hierarchical cluster analysis of immunohistologic data in DLBCL demonstrated that the expression profile of the LMO2 protein was similar to that of other GC-associated proteins (HGAL, BCL6, and CD10) but different from that of non-GC proteins (MUM1/IRF4 and BCL2). Our results warrant inclusion of LMO2 in multivariate analyses to construct a clinically applicable immunohistologic algorithm for predicting survival in patients with DLBCL.
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PMID:The oncoprotein LMO2 is expressed in normal germinal-center B cells and in human B-cell lymphomas. 1703 24

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.
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PMID:Molecular characterization of human multiple myeloma cell lines by integrative genomics: insights into the biology of the disease. 1717 82

Knockout and transgenic studies in mice demonstrate that normal somatic tissues redundantly express 3 cyclin D proteins, whereas tumor cells seem dependent on a single overexpressed cyclin D. Thus, selective suppression of the individual cyclin D deregulated in a tumor represents a biologically valid approach to targeted cancer therapy. In multiple myeloma, overexpression of 1 of the cyclin D proteins is a ubiquitous feature, unifying at least 7 different initiating genetic events. We demonstrate here that RNAi of genes encoding cyclin D1 and cyclin D2 (CCND1 and CCND2, respectively) inhibits proliferation and is progressively cytotoxic in human myeloma cells. By screening a chemical library using a cell-based assay for inhibition of CCND2 trans-activation, we identified the plant cytokinin kinetin riboside as an inhibitor of CCND2 trans-activation. Kinetin riboside induced marked suppression of CCND2 transcription and rapidly suppressed cyclin D1 and D2 protein expression in primary myeloma cells and tumor lines, causing cell-cycle arrest, tumor cell-selective apoptosis, and inhibition of myeloma growth in xenografted mice. Mechanistically, kinetin riboside upregulated expression of transcription repressor isoforms of cAMP-response element modulator (CREM) and blocked both trans-activation of CCND2 by various myeloma oncogenes and cis-activation of translocated CCND1, suggesting induction of an overriding repressor activity that blocks multiple oncogenic pathways targeting cyclin D genes. These data support targeted repression of cyclin D genes as a therapeutic strategy for human malignancies.
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PMID:Identification of kinetin riboside as a repressor of CCND1 and CCND2 with preclinical antimyeloma activity. 1843 19

Multiple myeloma (MM) is an incurable hematological malignancy. Different studies demonstrated the occurrence of genetic and epigenetic alterations in MM. The aberrant methylation is one of the most frequent epigenetic alterations in human genome. This study evaluated the aberrant methylation status of 20 genes in 51 MM samples by quantitative methylation-specific PCR (QMSP) and compared the methylation profile with clinicopathological characteristics of the patients. The QMSP analyses showed that PTGS2 (100.0%), SFN (100.0%), CDKN2B (90.2%), CDH1 (88.2%), ESR1 (72.5%), HIC1 (70.5%), CCND2 (62.7%), DCC (45.1%) and TGFbetaR2 (39.2%) are frequently hypermethylated in MM while aberrant methylation of RARbeta (16.6%), MGMT (12.5%), AIM1 (12.5%), CDKN2A (8.3%), SOCS1 (8.3%), CCNA1 (8.3%) and THBS1 (4.1%) are rare events. There was no methylation of GSTP1, MINT31, p14ARF and RB1 in the samples tested. Hypermethylation of ESR1 was correlated positively with isotype IgA, while aberrant methylation of THBS1 correlated negatively with isotype IgG. Furthermore, hypermethylation of DCC and TGFbetaR2 were correlated with poor survival. The multivariate analysis showed ISS and TGFbetaR2 hypermethylation strongly correlated with poor outcome. This study represents the first quantitative evaluation of promoter methylation in MM and our data provide evidence that TGFbetaR2 hypermethylation, besides ISS, may be useful as prognostic indicator in this disease.
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PMID:TGFbetaR2 aberrant methylation is a potential prognostic marker and therapeutic target in multiple myeloma. 1954 9

Specific microRNA (miRNA) signatures have been associated with different cytogenetic subtypes in acute leukemias. This finding prompted us to investigate potential associations between genetic abnormalities in multiple myeloma (MM) and singular miRNA expression profiles. Moreover, global gene expression profiling was also analyzed to find correlated miRNA gene expression and select miRNA target genes that show such correlation. For this purpose, we analyzed the expression level of 365 miRNAs and the gene expression profiling in 60 newly diagnosed MM patients, selected to represent the most relevant recurrent genetic abnormalities. Supervised analysis showed significantly deregulated miRNAs in the different cytogenetic subtypes as compared with normal PC. It is interesting to note that miR-1 and miR-133a clustered on the same chromosomal loci, were specifically overexpressed in the cases with t(14;16). The analysis of the relationship between miRNA expression and their respective target genes showed a conserved inverse correlation between several miRNAs deregulated in MM cells and CCND2 expression level. These results illustrate, for the first time, that miRNA expression pattern in MM is associated with genetic abnormalities, and that the correlation of the expression profile of miRNA and their putative mRNA targets is useful to find statistically significant protein-coding genes in MM pathogenesis associated with changes in specific miRNAs.
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PMID:Deregulation of microRNA expression in the different genetic subtypes of multiple myeloma and correlation with gene expression profiling. 2005 51

A large series of plasma cell dyscrasias (n=2207) was examined for translocations which deregulate the MAF genes, t(14;20)(q32;q12) and t(14;16)(q32;q23), and their disease behavior was compared to a group characterized by the t(4;14)(p16;q32) where CCND2 is also up-regulated. The t(14;20) showed low prevalence in myeloma (27/1830, 1.5%) and smoldering myeloma (1/148, <1%) with a higher incidence in MGUS (9/193, 5% P=0.005). Strong associations with del(13) (76%), non-hyperdiploidy (83%) and gain of 1q (58%) were seen but no association with an IgA M-protein or absence of bone disease was noted. All three translocations were associated with poor outcome in myeloma, but strikingly all t(14;20) MGUS/smoldering myeloma cases (n=10) had stable, low level disease. In contrast, the 10 t(14;16) and 25 t(4;14) MGUS/smoldering myeloma cases were associated with both evolving and non-evolving disease. None of the associated genetic abnormalities helped to predict for progression from MGUS or smoldering myeloma.
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PMID:The t(14;20) is a poor prognostic factor in myeloma but is associated with long-term stable disease in monoclonal gammopathies of undetermined significance. 2041 Jan 85

MicroRNAs (miRNAs) are mostly located at cancer-associated genomic regions or in fragile sites, suggesting their important role in the pathogenesis of human cancers. Multiple myeloma (MM) is a cancer of plasma cells, the third most common cancer of the blood after lymphoma and leukaemia. There are several published reports on miRNAs in MM, however most used bone marrow rather than peripheral blood samples. The aim of this study is to characterise miRNA expression in normal and MM patients using peripheral blood samples as it is less invasive and is readily available from patients. Blood samples from 35 MM patients were analysed using the microarray method. We identified up-regulation of 36 miRNAs (57%) and down-regulation of 27 miRNAs (43%). We also identified the CCND2, HMGA2 and IGF1R genes were among the highly predictive target genes (P(CT) > 0.80) for most of the deregulated miRNAs. These genes are known to play important roles in MM as well as other cancers. Five miRNAs (let-7c, miR-16, miR- 449, miR-181a and miR-181b) were found to exhibit similar expression patterns (p < 0.05) in peripheral blood when compared to data obtained by using bone marrow aspirates from MM patients in other studies. In conclusion, our study has demonstrated that miRNAs are also present and differentially expressed in the peripheral blood of MM patients compared to controls and may potentially serve as candidate tumour biomarkers in MM. In particular, let-7c and miR-16 have been shown to be significantly expressed in the bone marrow.
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PMID:MicroRNA (miRNA) expression profiling of peripheral blood samples in multiple myeloma patients using microarray. 2342 76


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