Bone marrow stroma CD40 expression correlates with inflammatory mast cell infiltration and disease progression in splenic marginal zone lymphoma.
Splenic marginal zone lymphoma (SMZL) is a mature B-cell neoplasm characterized by rather indolent clinical course. However, nearly one third of patients experience a rapidly progressive disease with a 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. Here we investigate 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 unfavorable prognostic influence of dense CD40 expression by BM stromal cells, which involves the contribution of CD40 ligand (CD40L)-expressing bystander mast cells infiltrating SMZL BM aggregates. The CD40/CD40L-assisted crosstalk 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 proinflammatory conditions. Our study highlights a dynamic interaction, playing between nonneoplastic elements within the SMZL niche, toward disease progression.
Hematology Unit with Bone Marrow Transplantation and.
Giovanni
G
Franco
Carla
C
Guarnotta
Barbara
B
Frossi
Pier Paolo
PP
Piccaluga
Emanuela
E
Boveri
Alessandro
A
Gulino
Fabio
F
Fuligni
Alice
A
Rigoni
Rossana
R
Porcasi
Salvatore
S
Buffa
Elena
E
Betto
Ada Maria
AM
Florena
Vito
V
Franco
Emilio
E
Iannitto
Luca
L
Arcaini
Stefano Aldo
SA
Pileri
Carlo
C
Pucillo
Mario Paolo
MP
Colombo
Sabina
S
Sangaletti
Claudio
C
Tripodo
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D016158:Genes, p53; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D018442:Lymphoma, B-Cell, Marginal Zone / Q000209:etiology / Q000276:immunology* / Q000473:pathology*; D008297:Male; D008407:Mast Cells / Q000276:immunology* / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008875:Middle Aged; D011379:Prognosis; D059016:Tumor Microenvironment / Q000276:immunology
D019013:CD40 Antigens; D016207:Cytokines; D018836:Inflammation Mediators; D023201:CD40 Ligand