Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of human multiple myeloma patients classified using the TC system to provide a molecular characterization of the TC groups

ABSTRACT: PURPOSE. The deregulation of CCND1, CCND2 and CCND3 genes represents a common event in multiple myeloma (MM). The recently proposed TC classification grouped MM patients into five classes on the basis of their cyclins D expression profiles and the presence of the main translocations involving the immunoglobulin heavy-chain locus (IGH) at 14q32. In this study, we provide a molecular characterization of the identified TC groups. MATERIALS AND METHODS. The gene expression profiles of purified plasma cells from 50 MM cases were used to stratify the samples into the five TC classes and identify their transcriptional fingerprints. The cyclin D expression data were validated by means of real-time quantitative PCR analysis; fluorescence in-situ hybridization was used to investigate the cyclin D loci arrangements, and to detect the main IGH translocations and the chromosome 13q deletion. RESULTS. Class-prediction analysis identified 112 probe sets as characterizing the TC1, TC2, TC4 and TC5 groups, whereas the TC3 samples showed heterogeneous phenotypes and no marker genes. The TC2 group, which showed extra copies of the CCND1 locus and no IGH translocations or the chromosome 13q deletion, was characterized by the overexpression of genes involved in protein biosynthesis at translational level. A meta-analysis of published datasets validated the identified gene expression signatures. CONCLUSIONS. Our data contribute to the understanding of the molecular and biological features of distinct MM subtypes. The identification of a distinctive gene expression pattern in TC2 patients may improve risk stratification and indicate novel therapeutic targets. Experiment Overall Design: This series of microarray experiments contains the gene expression profiles of purified plasma cells (PCs) obtained from 50 newly diagnosed multiple myeloma (MM). PCs were purified from bone marrow specimens, after red blood cell lysis with 0.86% ammonium chloride, using CD138 immunomagnetic microbeads. The purity of the positively selected PCs was assessed by morphology and flow cytometry and was > 90% in all cases. 5 micrograms of total RNA was processed and hybridized to the Affymetrix HG-U133A chip following the manufacturer's instructions.

ORGANISM(S): Homo sapiens

DISEASE(S): multiple myeloma TC3

SUBMITTER: Antonino Neri

PROVIDER: E-GEOD-2912 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Molecular classification of multiple myeloma: a distinct transcriptional profile characterizes patients expressing CCND1 and negative for 14q32 translocations.

Agnelli Luca L Bicciato Silvio S Mattioli Michela M Fabris Sonia S Intini Daniela D Verdelli Donata D Baldini Luca L Morabito Fortunato F Callea Vincenzo V Lombardi Luigia L Neri Antonino A

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20050829 29

<h4>Purpose</h4>The deregulation of CCND1, CCND2 and CCND3 genes represents a common event in multiple myeloma (MM). A recently proposed classification grouped MM patients into five classes on the basis of their cyclin D expression profiles and the presence of the main translocations involving the immunoglobulin heavy chain locus (IGH) at 14q32. In this study, we provide a molecular characterization of the identified translocations/cyclins (TC) groups.<h4>Materials and methods</h4>The gene expre ...[more]

PMID: 16129847

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Project description:Currently, multiple myeloma (MM) patients are broadly grouped into a non-hyperdiploid Group (nh-MM), highly enriched for IgH translocations, or into a hyperdiploid Group (h-MM), which is typically characterized by trisomies of some odd-numbered chromosomes. We compared the miRNA expression profiles of these two groups and we identified 16 miRNAs that were downregulated in the h-MM group, relative to the nh-MM group. We found that target genes of the most differentially expressed miRNAs are directly involved in the pathogenesis of MM; specifically, the inhibition of hsa-miR-425, hsa-miR-152 and hsa-miR-24, which are all downregulated in h-MM, leads to the overexpression of CCND1, TACC3, MAFB, FGFR3 and MYC, which are the also the oncogenes upregulated by the most frequent IgH chromosomal translocations occurring in nh-MM. Importantly, we showed that the downregulation of these specific miRNAs and the upregulation of their targets also occur simultaneously in primary cases of h-MM. These data provide further evidence on the unifying role of cyclin C pathways deregulation as the key mechanism involved in the development of both groups of MM. Finally, they establish the importance of miRNA deregulation in the context of MM, thereby opening up the potential for future therapeutic approaches based on this molecular mechanism. miRNA expression profiling: The discovery series was composed of 53 CD138-positive de novo primary cases of Multiple Myeloma, of which 36 were classified as nh-MM and 17 as h-MM. Also included in this first analysis were 7 MM cell lines, six (JJN3, L363, OPM-2, K620, KMS28BM, KMS28PE) representing the nh-MM subtype and one (OH-2) as the model for h-MM. All samples, primary cases and cell lines, were labeled and hybridized in duplicate to the ‘8-pack’ Human miRNA Oligo Microarray G4470A (Agilent Technologies). We differentially expressed miRNA expression between the nh-MM and the h-MM subtypes were identified by standardized bioinformatics methods.

Project description:To date, little evidence of miRNA expression/deregulation in multiple myeloma (MM) has been reported. To characterize miRNA expression profiling of MM plasma cells (PCs) and integrate miRNA expression data with other molecular features of MM patients, global miRNA expression profiles were generated for PCs isolated from BM biopsies of 38 newly diagnosed MM, 2 plasma cell leukemia patients, and 3 healthy donors; the samples were also profiled for global gene expression, and nineteen of them underwent genome-wide DNA analysis using high-density SNP-microarrays. Differential miRNA expression patterns were mainly identified in association with the major IGH translocations: in particular, t(4;14) showed specific over-expression of let-7e, miR-125a-5p and miR-99b belonging to a cluster at 19q13.33. The occurrence of other lesions, such as 1q gain, 13q and 17p deletions, and hyperdiploidy, was less well characterized by specific miRNA signatures. Genome-wide analysis showed that some allelic imbalances led to the significantly altered expression of miRNAs located in the involved regions, such as let-7b at 22q13.31 loss and miR-142-3p at 17q22 gain. The integrative analysis based on computational target prediction, miRNA and mRNA profiling defined a network of putative functional miRNA-target regulatory relations supported by expression data. This series of microarray experiments contains the microRNA profiles of purified plasma cells (PCs) obtained from 3 normal donor (N), 38 multiple myeloma (MM) and 2 plasma cell leukemia (PCL) at diagnosis. PCs were purified from bone marrow specimens after red blood cell lysis with 0.86% ammonium chloride using CD138 immunomagnetic microbeads. The purity of the positively selected PCs was assessed by morphology and flow cytometry and was >90% in all cases. 500 nanograms of total RNA was processed in accordance with the manufacturer's protocols (Agilent Technologies) to generate Cy3-labeled RNA which were purified on chromatography columns (Micro Biospin 6, Bio-Rad, Hercules, CA) and hybridized on an Agilent microarray (G4470B) at 55Â°C for 17 hr in a rotating oven. Images at 5 um resolution were generated using an Agilent scanner G2505B. The Feature Extraction 9.5 software (Agilent Technologies) was used to obtain the raw microarray data. The human miRNAs included in the platform were annotated according to Sanger miRBase Release 12.0. After discarding non-human miRNAs, the data were normalized using the Aroma Light package for Bioconductor. To overcome scaling biases due to background subtraction, the data were converted to obtain positive values throughout the dataset, at a minimum value of 1. The global gene expression raw data used in this study was originally deposited as GSE13591 and renormalized for this study. The genome wide profile (DNA) analysis was originally deposited as GSE16121.

Dataset Information

Transcription profiling of human multiple myeloma patients classified using the TC system to provide a molecular characterization of the TC groups

Publications

Molecular classification of multiple myeloma: a distinct transcriptional profile characterizes patients expressing CCND1 and negative for 14q32 translocations.

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