Extracellular vesicles shed by follicular lymphoma B cells promote polarization of the bone marrow stromal cell niche

• DOI: 10.1182/blood.2020008791
• Publication Date: 2021-04-22T11:43:29Z
• Authors: Erwan Dumontet; Céline Pangault; David Roulois; Matthis Desoteux; Simon Léonard; Tony Marchand; Maelle Latour; Patricia Legoix; Damarys Loew; Florent Dingli; Joelle Dulong; Erwan Flecher; Cédric Coulouarn; Guillaume Cartron; Thierry Fest; Karin Tarte
• Keywords: 0301 basic medicine; B-Lymphocytes; Base Sequence; Tumor Necrosis Factor-alpha; Gene Expression Profiling; Lymphotoxin alpha1, beta2 Heterotrimer; Cell Polarity; [SDV.CAN]Life Sciences [q-bio]/Cancer; [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology; Bone Marrow Cells; Cell Differentiation; Mesenchymal Stem Cells; Cell Communication; Hematopoietic Stem Cells; Endocytosis; Up-Regulation; Gene Expression Regulation, Neoplastic; Extracellular Vesicles; 03 medical and health sciences; Phenotype; Humans; Stromal Cells; Lymphoma, Follicular; Signal Transduction

Abstract Follicular lymphoma (FL) originates in the lymph nodes (LNs) and infiltrates bone marrow (BM) early in the course of the disease. BM FL B cells are characterized by a lower cytological grade, decreased proliferation, and a specific phenotypic and subclonal profile. Mesenchymal stromal cells (MSCs) obtained from FL BM display a specific gene expression profile (GEP), including enrichment for a lymphoid stromal cell signature, and an increased capacity to sustain FL B-cell growth. However, the mechanisms triggering the formation of the medullar FL permissive stromal niche have not been identified. In the current work, we demonstrate that FL B cells produce extracellular vesicles (EVs) that can be internalized by BM-MSCs, making them more efficient to support FL B-cell survival and quiescence. Accordingly, EVs purified from FL BM plasma activate transforming growth factor β–dependent and independent pathways in BM-MSCs and modify their GEP, triggering an upregulation of factors classically associated with hematopoietic stem cell niche, including CXCL12 and angiopoietin-1. Moreover, we provide the first characterization of BM FL B-cell GEP, allowing the definition of the landscape of molecular interactions they could engage with EV-primed BM-MSCs. This work identifies FL-derived EVs as putative mediators of BM stroma polarization and supports further investigation of their clinical interest for targeting the crosstalk between BM-MSCs and malignant B cells.