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Single cell analysis of MYD88 L265P and MYD88 WT Waldenström macroglobulinemia (WM) patients

ABSTRACT: Single cell analysis of MYD88 L265P and MYD88 WT Waldenström macroglobulinemia (WM) patients

PROVIDER: PRJNA987446 | ENA |

REPOSITORIES: ENA

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Single cell analysis of MYD88 L265P and MYD88 WT Waldenström macroglobulinemia (WM) patients

Project description:To elucidate the differences occurring in the B cell composition between WM patients, we performed single cell RNA sequencing on CD19 + sorted cells from patients with MYD88 L265P versus MYD88 WT phenotype and compared them with two healthy controls.

2024-02-28 | GSE235723 | GEO

Waldenström Macroglobulinemia immune microenvironment

Project description:In this study, we evaluated clonal Waldenström macroglobulinemia cells with mapping of maturation stages of B cell lymphomagenesis concurrently with the innate and adaptive immune tumor microenvironment in active WM patients (newly diagnosed (NDWM, n = 19) and relapsed or relapsed/refractory (RRWM, n = 42) compared to 10 healthy donors (HD) by mass cytometry.

2022-12-13 | PXD038388 | Pride

Therapeutic Activation of G Protein-Coupled Estrogen Receptor 1 in Waldenström Macroglobulinemia

Project description:Activation of G protein-coupled estrogen receptor 1 (GPER1) is an attractive therapeutic strategy to treat a variety of human diseases, including cancer. Here, we show that GPER1 is remarkably upregulated in tumor cells derived from different cohorts of Waldenström Macroglobulinemia (WM) patients respect to normal B cells. Using the clinically relevant GPER1-selective small-molecule agonist G-1 (also named Tespria), we demonstrate that pharmacological activation of GPER1 leads to G2/M cell cycle arrest and apoptosis both in vitro and in vivo in animal model, even in the context of the protective bone marrow milieu. We report that activation of GPER1 triggers the TP53 pathway, which remains actionable during WM progression. This study identifies a novel druggable target in WM and paves the way for the clinical development of the GPER1 agonist G-1.

2024-07-01 | GSE207488 | GEO

A gene set signature for the risk of progression in IgM MGUS to Waldenström Macroglobulinemia by microarray of B cells and plasma cells

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

Halting the FGF/FGFR axis leads to anti-tumor activity in Waldenström’s Macroglobulinemia by silencing MYD88

Project description:The human fibroblast growth factor/fibroblast growth factor-receptor (FGF/FGFR) axis deregulation is largely involved in supporting the pathogenesis of hematologic malignancies, including Waldenström’s Macroglobulinemia (WM). WM is still an incurable disease, and patients succumb due to disease progression. Therefore, novel therapeutics designed to specifically target deregulated signaling pathways in WM are required. We aimed to investigate the role of FGF/FGFR blocking system in WM by using a pan-FGF trap molecule (NSC12). Wide-transcriptome profiling confirmed inhibition of FGFR-signaling in NSC12-treated WM cells; unveiling a significant inhibition of Myd88 also confirmed at protein level. Importantly, the NSC12-dependent silencing of Myd88 was functionally active, as it led to inhibition of Myd88-driven pathways, such as BTK and SYK, as well as the Myd88-downstream target HCK. Of note, both canonical and non-canonical NFB cascades were down-regulated in WM cells upon NSC12 treatment. Functional sequelae exerted by NSC12 in WM cells were studied, demonstrating significant inhibition of WM cell growth, induction of WM cell apoptosis, halting MAPK, JAK/STAT3 and PI3K-Akt pathways. Importantly, NSC12 exerted an anti-WM effect even in the presence of bone marrow microenvironment, both in vitro and in vivo. Our studies provide the evidence for using NSC12 as a specific FGF/FGFR system inhibitor, thus representing a novel therapeutic strategy in WM.

2021-08-27 | GSE155155 | GEO

Transcriptome analysis of in vitro generated plasmablasts dervied from Waldenström macroglobulinemia (WM) or heathly control B-cells

Project description:Transcriptome analysis of in vitro generated plasmablasts dervied from Waldenström macroglobulinemia (WM) or heathly control B-cells

| PRJNA586850 | ENA

Non-coding RNA analysis in IgM monoclonal gammopathies: an underrecognized role of microRNA and long non-coding RNA differentiating Waldenström macroglobulinemia from IgM-MGUS

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

Gene expression changes caused by the IRAK1/IRAK4 inhibitor R191 in cell lines of Waldenström’s macroglobulinemia

Project description:The L265P mutation in MYD88 is very frequent in tumor cells of Waldenström’s macroglobulinemia (WM), and activates NF-kappaB through IRAK1 and IRAK4. We examined the effect of the IRAK1/4 inhibitor R191 on two cell lines of WM. Gene expression profiling suggested that R191 reduced activity of AKT and mTOR signaling, consistent with other assays and functional studies. Other changes suggested reduced proliferation and MYC activity, and an ER stress response.

2019-11-01 | GSE106409 | GEO

Transcriptome analysis of in vitro generated plasmablasts dervied from Waldenström macroglobulinemia (WM) or heathly control B-cells

Project description:The ability to model WM B-cell differentiation using an in vitro system was validated in comparison to healthy cells. The stimuli used initially were CD40L and F(ab’)2 anti-IgG/M, a combination which mimics T-cell dependent activation. Using these conditions, WM B-cells generated mature plasma cells that closely resemble those from healthy controls. Since WM cells harbour the characteristic gain-of-function MYD88L265P mutation, it was also of interest to determine the impact of TLR signals on the differentiation process. In contrast to the expectation of enhanced survival, WM cells exhibited a profoundly deleterious response to R848 + F(ab’)2 anti-IgG/M stimulation, with a sharp decline in population from the initiation of culture and a failure to generate plasma cells. RNA sequencing was performed on material harvested from differentiating cells at day 6 of culture within the in vitro system to assess the underlying gene expression changes that accompanied the two types of stimulation. The samples consisted of 3 healthy controls with matched samples for both CD40L and R848 stimulation and a total of 6 WM samples. Examination of the transcriptomes revealed that WM plasmablasts exhibit elevated expression levels of genes associated with TLR and NF-κB signaling, but reduced levels of genes associated with plasma cell re-programming. This is particularly pronounced in cells treated with the TLR7 agonist R848, suggesting an uncoupling of TLR signaling from plasma cell differentiation in WM.

2020-05-13 | GSE139671 | GEO

Transcription profiling of human Waldenstroms macroglobulinemia CD19+ WM B cells (WM-BC) and CD138+ WM plasma cells (WM-PC) with those of normal CD19+ peripheral blood B cells (PB-BC), tonsil-BC (T-BC), CD138+ T-PC and bone marrow PC (N-PC) reveals biological insights into its pathophysiology

Project description:Waldenströms macroglobulinemia (WM) is a rare lymphoproliferative disorder with apparent morphologic and immunophenotypic heterogeneity and its origins are still poorly understood. In this study, using Gene-Expression Profiling (GEP), we compared the global mRNA expression patterns of CD19+ WM B cells (WM-BC) and CD138+ WM plasma cells (WM-PC) with those of normal CD19+ peripheral blood B cells (PB-BC), tonsil-BC (T-BC), CD138+ T-PC and bone marrow PC (N-PC). Experiment Overall Design: The sample cohort studied consisted of CD19-selected peripheral blood B cells (PB-BC; n = 7), tonsil B cells (T-BC; n = 7), bone marrow B cells from WM (WM-BC; n = 12), tonsil plasma cells (T-PC; n = 9), bone marrow plasma cells from healthy donors (N-PC; n = 10), WM plasma cells (WM-PC, n = 9), and MM plasma cells (MM-PC; n = 11).

2008-12-05 | E-GEOD-9656 | biostudies-arrayexpress

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