Molecular Clusters and Tumor-Immune Drivers of IgM Monoclonal Gammopathies
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PROVIDER: PRJNA974694 | ENA |
REPOSITORIES: ENA
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Project description:Purpose: IgM monoclonal gammopathy of undetermined significance (MGUS) and Waldenström macroglobulinemia (WM) represent a disease spectrum with highly varied therapeutic management, ranging from observation to chemoimmunotherapy. The current classification relies solely on clinical features and does not explain the heterogeneity that exists within each of these conditions. Further investigation is warranted to shed light on the biology that may account for the clinical differences. Experimental design: We used bone marrow (BM) clonal CD19+ and/or CD138+ sorted cells, matched BM supernatant, and peripheral blood serum from 32 patients (7 MGUS, 25 WM) to perform the first multi-omics approach including whole-exome sequencing, RNA sequencing, proteomics, metabolomics, and mass cytometry. Results: We identified three clusters with distinct pathway activation, immune content, metabolomic, and clinical features. Cluster 1 included only patients with WM and was characterized by transcriptional silencing of genes involved in cell cycle and immune response, enrichment of mitochondrial metabolism, infiltration of senescent T effector memory cells, and aggressive clinical behavior. Genetic/structural alterations of TNFAIP3 were distinct events of this cluster. Cluster 2 comprised both MGUS and WM patients with upregulation of inflammatory response, senescence and glycolysis signatures, increased activated T follicular helper and T regulatory cells, and indolent clinical behavior. Cluster 3 also included both MGUS and WM patients and exhibited intermediate features, including proliferative and inflammatory signaling, as well as glycolysis and mitochondrial metabolism.
2023-12-08 | GSE232994 | GEO
Project description:Waldenström macroglobulinemia (WM), is a rare non-Hodgkin lymphoma preceded by a clinically asymptomatic benign monoclonal gammopathy of undetermined significance (IgM-MGUS). The factors underlying the malignant progression between these two IgM-monoclonal gammopathies remain poorly understood. The non-coding genome is increasingly recognized as an important driver of disease pathogenesis, and there remains a lack of exploration of the influence of non-coding RNAs within the IgM-monoclonal gammopathy disease spectrum. The present study explores the role of microRNA (miRNA) and long non-coded RNA (lncRNA) in IgM-gammopathies and specifically elucidates potentially regulated protein-coding genes and pathways. A comprehensive analysis of miRNA, lncRNA and protein-coding coding genes was conducted on 28 subjects, 17 patients with WM, 6 patients with IgM-MGUS, and 5 normal controls. Differential expression analysis revealed a number of dysregulated miRNA and lncRNA between IgM-gammopathies compared to normal controls and specifically between IgM-MGUS and WM. Pathway analysis was conducted utilizing differentially expressed mRNA with correlated biological expression of targeting miRNA. Here, a number of pathways were implicated influencing a gamut of cellular functions, including cell signaling, metabolism, replication, and immune regulation in both WM compared to IgM-MGUS and IgM-gammopathies compared to controls. This report is additionally one of the first published analyses of lncRNAs in WM, where we demonstrate a number of lncRNA associated with transcription and apoptosis regulation genes in WM compared to IgM-MGUS. This study highlights the role of non-coding RNA in IgM-gammopathies and the potential to recognize novel targets which may halt or slow the malignant progression between these two diseases.
2023-12-08 | GSE232995 | GEO
Project description:A highly recurrent, somatic L265P mutation in the TIR domain of the signaling adapter MYD88 constitutively activates NF-kB. It occurs in nearly all human patients with Waldenström’s macroglobulinemia (WM), a B cell malignancy caused by IgM-expressing cells. Here we introduced an inducible leucine to proline point mutation into the mouse Myd88 locus, at the orthologous position L252P. When the mutation was introduced early during B cell development, B cells developed normally. However, IgM-expressing plasma cells accumulated with age in spleen and bone, leading to more than 20-fold elevated serum IgM titers. When introduced into germinal center B cells in the context of an immunization, the Myd88L252P mutation caused prolonged persistence of antigen-specific serum IgM and elevated numbers of antigen-specific IgM plasma cells. Myd88L252P-expressing B cells switched normally, but plasma cells expressing other immunoglobulin isotypes did not increase in numbers, implying that IgM expression may be required for the observed cellular expansion. In order to test whether the Myd88L252P mutation can cause clonal expansions, we introduced it into a small fraction of CD19-positive B cells. In this scenario, five out of five mice developed monoclonal IgM serum paraproteins accompanied by an expansion of clonally related plasma cells that expressed mostly hypermutated VDJ regions. Taken together, our data suggest that the Myd88L252P mutation is sufficient to promote aberrant survival and expansion of IgM-expressing plasma cells which in turn can cause IgM monoclonal gammopathy of undetermined significance (MGUS), the premalignant condition that precedes WM. References: 1. Shevchenko A, Tomas H, Havli J, Olsen JV, Mann M. In-gel digestion for mass spectrometric characterization of proteins and proteomes. Nat Protoc (2006) 1:2856–2860. doi:10.1038/nprot.2006.468, 2. Rappsilber J, Mann M, Ishihama Y. Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat Protoc (2007) 2:1896–1906. doi:10.1038/nprot.2007.261, 3. Cox J, Neuhauser N, Michalski A, Scheltema RA, Olsen JV, Mann M. Andromeda: A Peptide Search Engine Integrated into the MaxQuant Environment. J Proteome Res (2011) 10:1794–1805. doi:10.1021/pr101065j, 4. Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol (2008) 26:1367–1372. doi:10.1038/nbt.1511.
2020-11-06 | PXD017292 | Pride
Project description:Non-coding RNA analysis in IgM monoclonal gammopathies: an underrecognized role of microRNA and long non-coding RNA differentiating Waldenström macroglobulinemia from IgM-MGUS
| PRJNA974696 | ENA
Project description:IgM monoclonal gammopathy of undetermined significance (IgM MGUS) is an early precursor stage of the rare lymphoma Waldenström Macroglobulinemia (WM). Although comparative gene expression studies on WM, IgM MGUS, and normal B cells identified several genes differently expressed, reliable predictors of progression from IgM MGUS to WM have not yet been identified. We performed a microarray study on CD19+ and CD138+ cells of WM vs. IgM MGUS vs. CTRLs to determine gene signatures for both cell populations. We demonstrated that hematopoietic antigens, cell-adhesion molecules, Wnt signaling, BCR signaling, calcium signaling, coagulation cascade, and pathways responsible for cell cycle and proliferation were significantly enriched for genes expressed in B cells of WM vs. IgM MGUS vs. CTRLs. Notably, we showed nine genes which displayed the same expression levels in both WM and IgM MGUS compared to CTRLs, suggesting their possible role in the risk of transformation in IgM MGUS to WM.
2021-04-09 | GSE171739 | GEO
Project description:Breast Cancer - immune clusters - RNA-seq
| PRJNA558331 | ENA
Project description:In this study we use expression data from breast cancer tumors to define immune clusters in breast cancer.
Immune clusters have gradual levels of immune infiltration. In the intermediate immune infiltration cluster, we found a worse prognosis which is independent of known clinicopathological features. We also found the immune clusters associated with treatment response. Further using gene expression data and deconvolution algorithms to dissect the immune contexture of the clusters.
| EGAS00001003631 | EGA
Project description:Glycosylation represents a major post-translational modification of proteins that can influence their structure and function.Telesot immunoglobulin M (IgM) is an especially important product of the immune system because it is the main Abs in seum and plays a critical role against defense infection. However, little is known regarding site-specific N-glycan characteristics in teleost IgM , LC-ESI-MS/MS was used to analysis deglycopeptides and glycopeptides of grass carp serum IgM, and MALDI-MS was used to analysis released carbohydrates by PNGaseF diestion of grass carp serum IgM.
2018-11-29 | PXD010308 | Pride
Project description:We use expression data from breast cancer tumors to define immune clusters in breast cancer. Immune clusters have gradual levels of immune infiltration. In the intermediate immune infiltration cluster, we found a worse prognosis which is independent of known clinicopathological features. We also found the immune clusters associated with treatment response. Further we use gene expression data and deconvolution algorithms to dissect the immune contexture of the clusters.
2019-12-10 | GSE135298 | GEO
Project description:Temporal analysis (60, 180, 360 min) of B cells treated with Anti-IgM alone, terbutaline alone or Anti-IgM and terbutaline (all in triplicates). Keywords: other
2004-02-13 | GSE1021 | GEO