Genetically driven immune microenvironment states associate with therapeutic responses in MYD88 mutant lymphomas [scRNA-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE292177 | GEO | 2026/09/03
REPOSITORIES: GEO
Similar Datasets
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:Although information on the molecular pathogenesis of Waldenström’s Macroglobulinemia (WM) has greatly improved in recent years, the exact cellular origin and the mechanisms behind WM transformation from IgM MGUS remain undetermined. Here, we undertook an integrative phenotypic, molecular and genomic approach to study clonal B-cells from newly-diagnosed patients with IgM MGUS (n=22), smoldering (n=17), and symptomatic WM (n=10). Through principal-component-analysis of multidimensional flow cytometry data, we demonstrated overlapping phenotypic profiles between clonal B-cells from IgM MGUS, smoldering and symptomatic WM patients. Similarly, virtually no genes were significantly deregulated between FACS-sorted clonal B-cells from the three disease stages. Interestingly, while the transcriptome of the Waldenström’s clone was highly deregulated as compared to CD25-CD22+ normal B-cells, significantly less genes were differentially expressed and specific WM pathways down-regulated while comparing the transcriptome of the Waldenström’s clone vs. its normal phenotypic counterpart: CD25+CD22+dim B-cells. The frequency of specific copy number abnormalities [+4, del(6q23.3-6q25.3), +12, and +18q11-18q23] progressively increased from IgM MGUS and smoldering WM vs. symptomatic WM (18% vs. 20% and 73%, respectively; P =.008), suggesting a multistep transformation of clonal B-cells that albeit benign (i.e.: IgM MGUS and smoldering WM), already harbor the phenotypic and molecular signatures of the malignant Waldenström’s clone.
2015-05-06 | GSE61650 | GEO
Project description:Although information on the molecular pathogenesis of Waldenström’s Macroglobulinemia (WM) has greatly improved in recent years, the exact cellular origin and the mechanisms behind WM transformation from IgM MGUS remain undetermined. Here, we undertook an integrative phenotypic, molecular and genomic approach to study clonal B-cells from newly-diagnosed patients with IgM MGUS (n=22), smoldering (n=17), and symptomatic WM (n=10). Through principal-component-analysis of multidimensional flow cytometry data, we demonstrated overlapping phenotypic profiles between clonal B-cells from IgM MGUS, smoldering and symptomatic WM patients. Similarly, virtually no genes were significantly deregulated between FACS-sorted clonal B-cells from the three disease stages. Interestingly, while the transcriptome of the Waldenström’s clone was highly deregulated as compared to CD25-CD22+ normal B-cells, significantly less genes were differentially expressed and specific WM pathways down-regulated while comparing the transcriptome of the Waldenström’s clone vs. its normal phenotypic counterpart: CD25+CD22+dim B-cells. The frequency of specific copy number abnormalities [+4, del(6q23.3-6q25.3), +12, and +18q11-18q23] progressively increased from IgM MGUS and smoldering WM vs. symptomatic WM (18% vs. 20% and 73%, respectively; P =.008), suggesting a multistep transformation of clonal B-cells that albeit benign (i.e.: IgM MGUS and smoldering WM), already harbor the phenotypic and molecular signatures of the malignant Waldenström’s clone.
2015-05-05 | GSE61597 | GEO
Project description:Although information on the molecular pathogenesis of Waldenström’s Macroglobulinemia (WM) has greatly improved in recent years, the exact cellular origin and the mechanisms behind WM transformation from IgM MGUS remain undetermined. Here, we undertook an integrative phenotypic, molecular and genomic approach to study clonal B-cells from newly-diagnosed patients with IgM MGUS (n=22), smoldering (n=17), and symptomatic WM (n=10). Through principal-component-analysis of multidimensional flow cytometry data, we demonstrated overlapping phenotypic profiles between clonal B-cells from IgM MGUS, smoldering and symptomatic WM patients. Similarly, virtually no genes were significantly deregulated between FACS-sorted clonal B-cells from the three disease stages. Interestingly, while the transcriptome of the Waldenström’s clone was highly deregulated as compared to CD25-CD22+ normal B-cells, significantly less genes were differentially expressed and specific WM pathways down-regulated while comparing the transcriptome of the Waldenström’s clone vs. its normal phenotypic counterpart: CD25+CD22+dim B-cells. The frequency of specific copy number abnormalities [+4, del(6q23.3-6q25.3), +12, and +18q11-18q23] progressively increased from IgM MGUS and smoldering WM vs. symptomatic WM (18% vs. 20% and 73%, respectively; P =.008), suggesting a multistep transformation of clonal B-cells that albeit benign (i.e.: IgM MGUS and smoldering WM), already harbor the phenotypic and molecular signatures of the malignant Waldenström’s clone. Copy number analysis using the Affymetrix CytoScan 750K Array to study clonal B-cells from newly-diagnosed patients with IgM MGUS, smoldering, and symptomatic WM. Peripheral T-cells from paired and unpaired controls were also assessed.
2015-05-06 | E-GEOD-61650 | biostudies-arrayexpress
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:Although information on the molecular pathogenesis of Waldenström’s Macroglobulinemia (WM) has greatly improved in recent years, the exact cellular origin and the mechanisms behind WM transformation from IgM MGUS remain undetermined. Here, we undertook an integrative phenotypic, molecular and genomic approach to study clonal B-cells from newly-diagnosed patients with IgM MGUS (n=22), smoldering (n=17), and symptomatic WM (n=10). Through principal-component-analysis of multidimensional flow cytometry data, we demonstrated overlapping phenotypic profiles between clonal B-cells from IgM MGUS, smoldering and symptomatic WM patients. Similarly, virtually no genes were significantly deregulated between FACS-sorted clonal B-cells from the three disease stages. Interestingly, while the transcriptome of the Waldenström’s clone was highly deregulated as compared to CD25-CD22+ normal B-cells, significantly less genes were differentially expressed and specific WM pathways down-regulated while comparing the transcriptome of the Waldenström’s clone vs. its normal phenotypic counterpart: CD25+CD22+dim B-cells. The frequency of specific copy number abnormalities [+4, del(6q23.3-6q25.3), +12, and +18q11-18q23] progressively increased from IgM MGUS and smoldering WM vs. symptomatic WM (18% vs. 20% and 73%, respectively; P =.008), suggesting a multistep transformation of clonal B-cells that albeit benign (i.e.: IgM MGUS and smoldering WM), already harbor the phenotypic and molecular signatures of the malignant Waldenström’s clone. Normal bone marrow CD25+ B-cells, Clonal B-Cells from IgM Monoclonal Gammopathy of Undetermined Significance, and Clonal B-Cells from Waldenström's Macroglobulinemia
2015-05-05 | E-GEOD-61597 | biostudies-arrayexpress
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: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:The interaction between lymphoma cells and immune microenvironment cells and the impact of this functional interplay on therapeutic responses remain unexplored. Here we utilized murine models with oncogenically active MYD88 and additional genetic lesions co-triggered at selected B-cell stages to generate human-like lymphomas harboring MYD88L265P mutation. Lymphomas exhibited behaviors ranging from clinically indolent small-cell tumors to aggressive diffuse large B-cell lymphoma (DLBCL). Thus, genetically diverse lymphoma cells employed distinct immune evasion mechanisms that shaped unique lymphoma microenvironment (LME) states, whereby clonally expanded T-cells functioned as a double-edged sword, either sustaining indolent lymphoma cell survival or promoting antitumor responses in DLBCL. Consequently, efficacy of standard-of-care and novel immunotherapies was determined by individual T-cell features. Furthermore, experimental targeting of newly identified immune mechanisms improved therapeutic responses in vivo. Our results elucidate genetically-driven LME landscapes that influence therapeutic outcomes across distinct lymphoma subtypes, providing a proof-of-concept for personalized treatment based on immune information.
2026-09-03 | GSE288502 | GEO
Project description:Majority of B cell malignancies originate in the germinal centers (GCs), where B cells undergo activation to mutationally diversify their antibody genes and switch from the default Immunoglobulin M (IgM) or IgD B cell receptor (BCR) to IgG, IgA or IgE BCR isotypes. Similar to normal B cells, malignant B cells rely on signals emanating from the BCR for their survival and growth. While studies have primarily focused on elucidating the functions of IgM-mediated signaling in lymphoma pathogenesis, GC-derived lymphomas also express IgG and IgA BCR isotypes that greatly differ from IgM in their signaling potential. How these distinct non-IgM BCRs contribute to the pathogenesis of B cell malignancies is not well understood. Interestingly, B cell lymphoma patients expressing IgG BCR isotypes show better prognosis and survival than those expressing IgM BCR isotype. Consistent with this, we show that Diffuse Large B Cell Lymphoma (DLBCL) patients with higher IgG1 expression are associated with lower stages of disease than those with higher IgM expression. To directly test the roles of distinct BCR isotypes, we developed isogenic lymphoma cells that either express IgM or IgG1 BCRs. Interestingly, the IgG1-switched lymphoma cells fail to form tumors in mice whereas their IgM counterparts establish aggressive tumors. Moreover, co-transplantation of IgG1 and IgM expressing human and mouse lymphoma cells leads to emergence of tumors expressing IgM (and not IgG1), demonstrating that IgM BCRs are strongly favored over IgG1. Mechanistically, IgG1 expressing lymphoma cells and non-malignant activated B cells have reduced survival which is associated with a dysfunctional mitochondrial state triggered by stronger calcium responses in IgG1 in comparison to IgM cells. Genetic reversal of IgG1 to IgM or pharmacological dampening of the calcium signaling is sufficient to correct the mitochondrial defects and rescue the survival of IgG1 B cells. Our findings demonstrate that distinct BCR isotypes are inherently unique in their activities and can differentially impact B cell lymphoma pathogenesis.
2025-04-18 | GSE249885 | GEO