Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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MiRNA profiling of multiple myeloma, MGUS, multiple myeloma cell lines and normal plasma cells

ABSTRACT: miRNA profiling in multiple myeloma - microRNAs represent a class of noncoding regulators of gene expression implicated in several biological and pathophysiological processes, including cancer. We investigate here their role in multiple myeloma using miChip-arrays interrogating 559 miRNAs in 92 purified myeloma-, MGUS-, normal plasma cell- and myeloma cell line samples. Impact on gene expression is assessed by Affymetrix U133 2.0 DNA-microarrays in 741 samples including two cohorts of 332 and 345 myeloma patients; chromosomal aberrations are assessed by iFISH, survival for 247 and 345 patients undergoing up-front high-dose therapy and autologous stem cell transplantation. Compared to normal plasma cells, 67/559 (12%) miRNAs are differentially expressed with fold changes of 4.6 to -3.1 in myeloma-, 20 (3.6%) in MGUS-samples, and three (0.5%) between MGUS- and myeloma-samples. Expression of miRNAs is associated with biological and pathophysiological parameters, i.e. proliferation, chromosomal aberrations, e.g. t(4;14), tumor mass, and gene expression-based high-risk scores. This holds true for target-gene signatures of regulated mRNAs. miRNA-expression confers prognostic significance for event-free (72/559) and overall survival (69/559), as do respective target-gene signatures. In conclusion, the miRNome of myeloma confers a pattern of small changes of individual miRNAs compared to normal plasma cells impacting on gene expression, biological functions, and survival.

ORGANISM(S): Homo sapiens

SUBMITTER: Tobias Meissner

PROVIDER: E-MTAB-1363 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:We have used genome-wide methylation microarrays to analyze differences in CpG methylation patterns in cells relevant to the pathogenesis of myeloma plasma cells, including B cells, normal plasma cells, MGUS, presentation myeloma, and plasma cell leukemia (PCL). We show that methylation patterns in these cell types are capable of distinguishing non-malignant from malignant cells and that the main reason for this difference is hypomethylation of the genome at the transition from MGUS to presentation myeloma. In addition, gene-specific hypermethylation was evident at the myeloma stage. Differential methylation was also evident at the transition from myeloma to PCL with re-methylation of the genome, specifically of genes involved in cell-cell signaling and cell adhesion, which may contribute to independence from the bone marrow microenvironment. There was a high degree of methylation variability within presentation myeloma samples and this was associated with the cytogenetic differences between samples. More specifically, we found that methylation subgroups were defined by translocations and hyperdiploidy, with t(4;14) myeloma having the largest impact on DNA methylation. Two groups of hyperdiploid samples were identified, based on unsupervised clustering, which had an impact on overall survival. Overall, DNA methylation has a large impact on disease progression and on myeloma cytogenetic subgroups. Bone marrow aspirates were obtained after informed consent. B cells (n=6) from normal individuals were selected from peripheral blood using CD19. Plasma cells (PC) from non-myeloma patients (normal plasma cell controls, n=3) as well as MGUS (n=4) and presentation myeloma patients (n=161) were selected to a purity of >90% using CD138 microbeads and magnet-assisted cell sorting (Miltenyi Biotech, Bisley, UK). Samples from PCL patients (n=7) were not CD138 selected but contained >90% plasma cell infiltration as determined by microscopy. In order to achieve a sufficient quantity of DNA some normal plasma cell control samples were pooled.

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MiRNA profiling of multiple myeloma, MGUS, multiple myeloma cell lines and normal plasma cells

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