Identification of circulating microRNAs as diagnostic biomarkers for use in multiple myeloma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
DISEASE(S): MGUS
SUBMITTER: Christopher Jones
PROVIDER: E-MTAB-1254 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Multiple myeloma is preceded by monoclonal gammopathy of undetermined significance (MGUS). Serum markers are currently used to stratify MGUS patients into clinical risk groups. A molecular signature predicting MGUS progression has not been produced. We have explored the use of gene expression profiling to risk-stratify MGUS and developed an optimized signature based on large samples with long-term follow-up. Microarray analysis of mRNA from MGUS patients with stable disease and MGUS patients that progressed to MM within 10 years, was used to define a molecular signature of MGUS risk.
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Project description:Fibroblasts are a key cellular component of tumour microenvironment, along with other stromal cells playing a critical role in disease initiation and progression (1). In this study, bone marrow fibroblasts deriving from patients with monoclonal gammopathy of undetermined significance (MGUS) or active multiple myeloma (MM) were subjected to global gene expression analysis, in order to identify progression-associated alterations of gene expression. Through immunoselection procedures, primary coltures of bone marrow fibroblasts were established from bone marrow aspirate of 18 patients fullfilling the International Myeloma Working Group diagnostic criteria for MM (n=10) and MGUS (n=8). Differentially expressed genes were investigated through cDNA microarray (21,329 70-mer oligonucleotides; dual-label competitive hybridization), using the reference design as experimental protocol and t-test statistics for identifying differentially expressed genes. A number of genes functionally involved in survival, proliferation, motility, inflammation and angiogenesis were found to be up-regulated in bone marrow fibroblasts from MM patients with respect to MGUS patients. In parallel, several genes were down-regulated in MM fibroblasts. Overall, bone marrow fibroblasts from MM patients show a distinct gene expression pattern that differentiates them from bone marrow fibroblasts of MGUS. The observation of differentially expressed genes indicates an activation state of fibroblasts in MM, which very likely concur to determine a microenvironment supporting disease progression. 1) 1. Kalluri R, Zeisberg M: Fibroblasts in cancer. Nat Rev Cancer 2006; 6: 392 â401. Bone marrow fibroblasts deriving from patients with monoclonal gammopathy of undetermined significance (MGUS) and active multiple myeloma (MM), were provided by A.Vacca, (Department of Biomedical Sciences and Human Oncology, Università degli Studi di Bari Aldo Moro, Italy). Briefly, primary coltures of bone marrow fibroblasts were established through immunoselection procedures on aspirates of 18 patients fullfilling the IMWG diagnostic criteria for active MM (n=10) and MGUS (n=8). Total RNA was extracted from each primary culture (test samples), and 1 μg-aliquots of RNA from MGUS samples were pooled to obtain the reference RNA. Linear amplification of mRNA and fluorescent labelling of cDNA targets (Cy5, MM and MGUS test samples; Cy3, reference RNA) were performed by using the Amino Allyl MessageAmp II aRNA Amplification Kit (Ambion), and examined on Micro-CRIBI Human Oligo Array (Operon V2.0) microarrays. Array scanning was carried out using a VersArray ChipReader® 5μm dual confocal laser scanner with VersArray ChipReader v3.1 analysis software , while row scanner images were analyzed with VersArray Analyzer Software v4.5 (Bio-Rad Laboratories) using media pixel intensities for each spot. Global background was subtracted by biquadratic polynomial approximation, and cross-channel normalization was performed by local regression (LOESS); logarithmic transformation was then performed for each expression level.
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Project description:Multiple myeloma (MM) is a hematopoietic malignancy.Based on its laboratory and clinical presentation it can be summarized as MGUS, smoldering myeloma, and multiple myeloma. Previous studies have shown that the expression levels of miRNAs in different stages of the disease are different and exosomes are involved in modulating the progression and the metastasis of cancers through miRNAs. This study analyzes the expression levels of miRNAs in healthy individuals and myeloma bone marrow serum exosomes.
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Project description:Multiple myeloma is a multi-stage disease. Based on its laboratory and clinical presentation it can be summarized as MGUS, smoldering myeloma, and multiple myeloma. Previous studies have shown that the expression levels of miRNAs in different stages of the disease are different. This study analyzes the expression levels of miRNAs in healthy individuals and myeloma serum exosomes. We used microarrays to detail the miRNAs expressionin between 12 healthy individuals and 12 multiple myeloma and identified distinct classes of dys-regulated genes.
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Project description:Multiple myeloma (MM) is an incurable hematological malignancy of mature B lymphocytes. In this study patients with MGUS, SMM and MM followed in two hematology departments were enrolled. Extracellular vesicles were isolated from bone marrow (BM) and peripheral blood (PB) followed by mass spectrometry based bottom up proteomics.
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Project description:Multiple myeloma (MM) evolves from highly prevalent premalignant condition termed Monoclonal Gammopathy of Undetermined Significance (MGUS). We report an MGUS-MM phenotype arising in transgenic mice with Emu-directed expression of the unfolded protein/ER stress response and plasma cell development spliced isoform factor XBP-1s. Emu-XBP-1s elicited elevated serum Ig and IL-6 levels, skin alterations and with advancing age, a significant proportion of Emu-xbp-1s transgenic mice develop features diagnostic of human MM including bone lytic lesions. Transcriptional profiles of Emu-xbp-1s B lymphoid and MM cells show aberrant expression of genes known to be dysregulated in human MM including Cyclin D1, MAF, MAFB, and APRIL. This genetic model coupled with documented frequent XBP-1s overexpression in human MM serve to implicate chronic XBP-1s dysregulation in the development of this common and lethal malignancy. Keywords: XBP-1, MGUS, multiple myeloma, transgenic mouse
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Project description:To determine the cell types and their transcriptional alterations during multiple myeloma progression from its precursor conditions, ie. monoclonal gammopathy of undetermined significance (MGUS), and smoldering multiple myeloma (SMM), we used single-cell RNA sequencing (scRNA-seq) to analyze the bone marrow aspirate samples from 4 newly diagnosed multiple myeloma, 6 MGUS and 4 SMM patients as well as 5 healthy donors.
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Project description:Gene expression profiling of CD138 purified bone marrow plasma cells of normal donnors, previoulsy untreated MGUS and multiple myeloma patients, and myeloma cell lines
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Project description:To characterize epigenomic changes during the transformation of normal plasma cells to myeloma, we used the HELP assay to analyze the methylome of CD138+ cells from 56 subjects representing premalignant (MGUS), early and advanced stages of myeloma as well as healthy controls. Plasma cells from premalignant and early stages of myeloma were characterized by striking, widespread hypomethylation. CD138+ selected bone marrow plasma cells from 8 normal donors, 11 patients with monoclonal gammopathy of uncertain significance (MGUS), 4 patients with smoldering myeloma (SMM), 13 patients with newly diagnosed myeloma (NEWMM), 16 patients with relapsed myeloma (REL), including 2 patients with serial samples, and 2 patients in clinical complete remission (REM) were analyzed using the HELP assay [HpaII tiny fragment Enrichment by Ligation-mediated PCR].
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