Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease [methylation II]
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE137416 | GEO | 2020/11/25
REPOSITORIES: GEO
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Project description:Genome wide DNA methylation profiling of bone marrow-derived mesenchymal stromal cells from healthy donors (n=11), monoclonal gammopathy of undetermined significance (MGUS) (n=10), smoldering myeloma (SMM) (n=8), multiple myeloma (MM) (n=9) patients, and healthy donors exposed to the MM.1S cell line (n=3). The Illumina Infinium MethylationEPIC Beadchip was used to obtain DNA methylation profiles across approximately 850,000 CpGs in this cell type.
2020-11-25 | GSE137360 | GEO
Project description:Gene expression profiling of bone marrow-derived mesenchymal stromal cells from healthy donors (n=8), monoclonal gammopathy of undetermined significance (MGUS) (n=10), smoldering myeloma (SMM) (n=10) and multiple myeloma (MM) (n=24) patients. Gene expression profile of MSCs was obtained using high density oligonucleotide microarrays (Human Gene 1.0 ST Array from Affymetrix).
2020-11-25 | GSE137369 | GEO
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.
2024-07-04 | GSE271107 | GEO
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].
2013-04-03 | E-GEOD-43860 | biostudies-arrayexpress
Project description:Smoldering myeloma (SMM) is a pre-malignant monoclonal gammopathy with a 10% annual risk to progress to active multiple myeloma (MM). SMM diagnostic criteria, as well of those of others monoclonal gammopathies, have been updated by the International Myeloma Working Group (IMWG) in 2014. In particular, the previously defined “ultra high-risk” SMM (characterized by the presence of specific biomarkers associated with a ≥ 80% risk of progression to symptomatic MM within 2 years) has been included among patients with active MM. SMM is biologically heterogeneous, including a subset of patients with biological pre-malignancy and a subset with biological malignancy who have not yet developed organ damage, defined as onset of the classical CRAB criteria or Myeloma Defining Events (MDE). Thus, SMM encompassed patients with a very low rate of progression to symptomatic MM, similar to patients with monoclonal gammopathy of uncertain significance (MGUS), as well as patients who acquired organ damage and progress to active MM within the first year from diagnosis. The molecular mechanisms involved in the SMM to MM progression are still far to be fully understood. Genomic studies indicate that the genetic alterations that characterize MM patients are already present in SMM ones, who present similar mutational and copy number alteration load. However, few data are available on the transcriptional profiles of SMM patients in relationship to the progression to active MM, overall indicating minimal differential expression either in coding or non-coding RNA fraction. To date, robust data are still lacking which describe the transcriptional profiles of plasma cells (PCs) from paired samples obtained at the time of SMM and at MM onset. Herein, we compared the transcriptome of purified CD138+ PCs from paired samples of SMM patients progressed to active MM (P-SMM), aimed at describing any possible common transcriptional discrepancy that may help to understand the intra-patient disease evolution; at the same time, we investigated the transcriptional differences between P-SMM and a subset of non-progressed SMM (NP-SMM) at a minimum of 36 months.
2019-07-17 | GSE117847 | GEO
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
2007-04-09 | GSE6980 | GEO
Project description:Precursor states of Multiple Myeloma (MM) and its native tumor microenvironment need in-depth molecular characterization to better stratify and treat patients at risk. Using single-cell RNA sequencing of bone marrow cells from precursor stages, MGUS and smoldering myeloma (SMM), to full-blown MM alongside healthy donors, we demonstrate early immune changes during patient progression. We find NK cell abundance is frequently increased in early stages, and associated with altered chemokine receptor expression. As early as SMM, we show loss of GrK+ memory cytotoxic T-cells, and show their critical role in MM immunosurveillance in mouse models. Finally, we report MHC class II dysregulation in CD14+ monocytes, which results in T cell suppression in vitro. These results provide a comprehensive map of immune changes at play over the evolution of pre-malignant MM, which will help develop strategies for immune-based patient stratification.
2020-04-28 | GSE124310 | GEO
Project description:Multiple Myeloma (MM) is an incurable plasma cell malignancy primarily localized within the bone marrow (BM). It develops from a premalignant stage, monoclonal gammopathy of undetermined significance (MGUS), often via an intermediate stage, smoldering MM (SMM). The mechanisms of MM progression have not yet been fully understood, all the more because patients with MGUS and SMM already carry the same initial mutations found in MM cells. Over the last years, more and more importance has been attributed to the tumor microenvironment and its role in the pathophysiology of the disease. Adaptations of MM cells to the hypoxic conditions in the BM have been shown to contribute to a significant extent to MM progression, independently from the genetic predispositions of the tumor cells. To get deeper insights into such hypoxia-induced adaptations, we decided to investigate primary human MM cells. CD138-positive plasma cells freshly isolated from the BM of patients with different disease stages, comprising MGUS, SMM, and MM, were analyzed by proteome profiling using a Q Exactive orbitrap. Data previously obtained from peripheral B cells were included for comparative purposes. As a first, rather unexpected result, we were able to identify three clusters differentiating B cells as well as MM cells corresponding to less and more advanced disease stages. Comparing on the one hand B cells to MM cells, and on the other hand the two clusters of MM cells allowed us to determine transcription factors apparently involved in MM development and progression, as well as protein regulatory networks obviously related to metabolic adaptations and immune evasion strategies used by MM cells to overcome limitations imposed by hypoxia. Based on these results, new opportunities may arise for developing therapeutic strategies targeting the progression from less to more advanced stages of MM.
2019-02-27 | PXD010600 | Pride
Project description:Genetic events mediating transformation from the pre-malignant monoclonal gammopathies (MG) to multiple myeloma (MM) are unknown. To obtain a comprehensive genomic profile of MG from the early to the late stages we performed high resolution analysis on purified plasma cells from 20 MGUS, 20 smoldering MM (SMM) and 34 MM by high density 6.0 SNP-array.
2012-03-31 | E-GEOD-31339 | biostudies-arrayexpress
Project description:Tumor immune microenvironmental alterations occur early in multiple myeloma (MM) development. In this study, we aim to systematically characterize the tumor immune microenvironment (TME) and the tumor-immune interactions from precursor stages, i.e., monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), to newly diagnosed MM, comparing these to healthy donors. CIBERSORT analysis revealed proportions of 27 cell types, including 10 innate immune cells (monocytes, M0/M1/M2 macrophages, resting/activated dendritic cells, resting/activated mast cells, eosinophils, and neutrophils), 7 T cell subsets (CD8+ T cells, naive CD4+ T cells, resting/activated memory CD4+ T cells, follicular helper T cells, regulatory T cells, and gamma delta T cells), resting/activated NK cells, naive B cells, memory B cells, plasma cells, myeloma plasma cells, memory plasma cells, osteoblasts, osteoclasts and adipocytes. We removed plasma cells (PC) from the 100% total cell proportions to avoid bias resulting from different tumor burdens. We found that the proportions of neutrophils, mast cells, and monocytes account for the majority of innate immune cells and were decreased in NDMM and its precursor stages when compared with NBM. We noticed a significant abundance of M2 macrophages in NDMM, but not in the precursor stages. The proportion of CD8+ T cells was increased at the SMM and MM stages, and the proportion of activated memory CD4+ T cells continued to decrease from NBM to MGUS, SMM, and MM. We performed correlation analysis of immune cell proportions with the time of progression of MGUS and SMM patients. We observed neutrophil proportions were negatively correlated with the time to progression in SMM patients, indicating more neutrophils predict inferior outcomes for SMM patients. However, in NDMM patients, we observed that the neutrophil percentage was decreased in patients with high-risk status based on the 70-gene Prognostic Risk Score (GEP-70) or at stage III of International Staging System (ISS), and patients with high proportions of neutrophils had a significantly superior overall survival (OS) and event-free survival (EFS). For T cell populations, we observed that the proportions of CD8+ T cells were negatively correlated with the time of progression in SMM patients and the γδ T cells were positively correlated. We observed the proportions of γδ T cells were also positively correlated with the time of progression in MGUS patients. Consistent with the time-to-progression data, high-risk SMM patients showed higher proportions of CD8+ T cells and lower proportions of naïve CD4+ T cells and γδ T cells.
2024-11-22 | GSE276561 | GEO