Bone marrow stroma CD40 expression correlates with inflammatory mast cell infiltration and disease progression in splenic marginal zone lymphoma.

Splenic marginal zone lymphoma (SML) is a mature B-cell neoplasm characterized by rather indolent clinical course. However, nearly one third of patients experience a rapidly progressive disease with dismal outcome. Despite the characterization of clone genetics and the recognition of deregulated immunologic stimulation in the pathogenesis of SMZL, little is known about microenvironment dynamics and their potential biological influence on disease outcome. Herein we have investigated the effect of stroma-intrinsic features on SMZL disease progression by focusing on the microenvironment of the bone marrow (BM), which represents an elective disease localization endorsing diagnostic and prognostic relevance. We show that the quality of the BM stromal meshwork of SMZL infiltrates correlates with time to progression. In particular, we describe the unfavourable prognostic influence of dense CD40 expression by BM stromal cells, which involves the contribution of CD40L-expressing bystander mast cells infiltrating SMZL BM aggregates. The CD40/CD40L-assisted cross-talk between mesenchymal stromal cells and mast cells populating the SMZL microenvironment finds correlation in p53-/- mice developing SMZL and contributes to the engendering of detrimental pro-inflammatory conditions. Our study highlights a dynamic interaction playing between non-neoplastic elements within the SMZL niche, toward disease progression.