Dessauge Elise, Brauge Baptiste, Léonard Simon, Beyou Alicia, Laurent Camille, Isen Valentin, Barbier Nicolas, Monvoisin Céline, Lejeune Thomas, Destin Jérôme, Jouan Florence, Saout Judikael, Llamas-Gutierrez Francisco, Morschhauser Franck, Roulland Sandrine, Roulois David, Mourcin Frédéric, Tarte Karin
UMR 1236, University of Rennes, INSERM, Etablissement Français du Sang, Equipe Labellisée Ligue, Rennes, France.
Centre d'Immunologie de Marseille-Luminy, Aix-Marseille University, Centre National de la Recherche Scientifique, INSERM, Marseille, France.
Blood Adv. 2025 Jul 22;9(14):3455-3468. doi: 10.1182/bloodadvances.2024015616.
Bone marrow (BM) involvement is a common feature of germinal center-derived B-cell lymphomas and is associated with a poor prognosis. In particular, follicular lymphoma (FL) infiltrates the BM in 70% of cases, and analysis of in vitro-expanded FL BM mesenchymal stromal cells (MSCs) has revealed an extensive alteration of BM stromal cell phenotypic, transcriptomic, and functional profiles. However, the mechanisms underlying the direct interplay between lymphoma B cells and their permissive stromal niche in situ have not yet been identified. In this study, we identified a significant remodeling of extracellular matrix (ECM) composition and organization in the BM of patients with FL and in a murine model of lymphoma B-cell BM xenograft. In particular, murine leptin receptor (LepR+) MSCs were identified by single-cell RNA sequencing as engaged in a bidirectional cross talk with malignant B cells, triggering their specific and progressive reprogramming and commitment toward a phenotype resembling that of human ECM/transforming growth factor β (TGFβ) myofibroblastic cancer-associated fibroblasts (CAFs) and FL-CAFs. Kinetic analysis of FL BM samples showed that ECM and TGFβ deregulation persisted after treatment, suggesting it may contribute to disease persistence and relapse. Overall, this work sheds new light on the kinetics and mechanisms of BM stromal niche reshaping in B-cell lymphomas.
骨髓（BM）受累是生发中心来源的B细胞淋巴瘤的常见特征，且与预后不良相关。特别是，70%的滤泡性淋巴瘤（FL）病例会浸润骨髓，对体外扩增的FL骨髓间充质基质细胞（MSCs）的分析显示，骨髓基质细胞的表型、转录组和功能谱发生了广泛改变。然而，淋巴瘤B细胞与其原位允许性基质微环境之间直接相互作用的潜在机制尚未明确。在本研究中，我们在FL患者的骨髓以及淋巴瘤B细胞骨髓异种移植小鼠模型中，发现了细胞外基质（ECM）组成和组织的显著重塑。特别是，通过单细胞RNA测序鉴定出小鼠瘦素受体（LepR+）MSCs与恶性B细胞进行双向串扰，触发其特异性和渐进性重编程，并使其向类似于人类ECM/转化生长因子β（TGFβ）肌成纤维细胞癌相关成纤维细胞（CAFs）和FL-CAFs的表型转变。对FL骨髓样本的动力学分析表明，治疗后ECM和TGFβ失调持续存在，提示其可能导致疾病持续和复发。总体而言，这项工作为B细胞淋巴瘤中骨髓基质微环境重塑的动力学和机制提供了新的见解。
