Lymphoma B cells remodel bone marrow stromal cells into extracellular matrix-producing cancer-associated fibroblasts

• Lymphoma B cells trigger transcriptional reprogramming and deregulation of extracellular matrix organization in bone marrow stromal cells.

• Alteration of the tumor-supportive bone marrow stromal niche in follicular lymphoma persist after treatment.

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 been yet identified. In the current work, we identified a significant remodelling of extracellular matrix (ECM) composition and organization in the BM of FL patients and in a murine model of lymphoma B-cell BM xenograft. In particular, murine leptin receptor (LepR)pos MSCs were identified by scRNAseq as engaged in a bidirectional crosstalk with malignant B cells, triggering their specific and progressive reprogramming and commitment towards a phenotype resembling that of human ECM/TGFb myofibroblastic cancer-associated fibroblasts (myCAFs) and FL-CAFs. Kinetic analysis of FL BM samples showed that ECM and TGFb 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.