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

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

PROVIDER: PRJNA855909 | ENA |

REPOSITORIES: ENA

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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

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.

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

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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.

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Therapeutic activation of G protein-coupled estrogen receptor 1 in Waldenstrom Macroglobulinemia.

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

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