Lymphoma cell adhesion-induced expression of B cell-activating factor of the TNF family in bone marrow stromal cells protects non-Hodgkin's B lymphoma cells from apoptosis.
This study explores whether lymphoma cell adhesion-induced B cell-activating factor (BAFF) expression in bone marrow stromal cells (BMSCs) protects B lymphoma cells from apoptosis. We first showed protection of lymphoma cells from apoptosis by conditioned medium of a stromal cell-lymphoma cell coculture, either spontaneous or induced by mitoxantrone, implying a role for soluble factor(s) in lymphoma cell survival. Addition of BAFF counteracted mitoxantrone-induced apoptosis and elicited a reduction in spontaneous apoptosis in primary lymphomas, suggesting a role of BAFF in sustaining B-cell survival. Abundant BAFF was detected in the BMSC cell line (HS-5) and primary BMSCs by flow cytometry, RT-PCR and immunoblotting. BAFF levels were 20- to 200-fold higher in BMSCs than in lymphoma cells, and lymphoma cell adhesion to BMSCs augmented BAFF secretion twofold through upregulation of BAFF gene expression. Finally, neutralization of BAFF by TACI-Ig or depletion of BAFF by small hairpin RNA (shRNA) in BMSCs significantly enhanced lymphoma cell response to chemotherapy and overcame stroma-mediated drug resistance, suggesting that lymphoma cells use BMSC-derived BAFF as a survival factor. These findings support the hypothesis that lymphoma cells interact with BMSCs, resulting in stromal niches with high BAFF concentration, and identify BMSC-derived BAFF as a functional determinant for B lymphoma cell survival in the bone marrow environment.
Department of Oncologic Sciences and Experimental Therapeutics Program, H Lee Moffitt Cancer Center, University of South Florida, Tampa, FL 33613, USA.
T
T
Lwin
L A
LA
Crespo
A
A
Wu
S
S
Dessureault
H B
HB
Shu
L C
LC
Moscinski
E
E
Sotomayor
W S
WS
Dalton
J
J
Tao
D017209:Apoptosis; D053264:B-Cell Activating Factor / Q000235:genetics*; D001854:Bone Marrow Cells; D002448:Cell Adhesion; D002450:Cell Communication; D002470:Cell Survival; D018920:Coculture Techniques; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016393:Lymphoma, B-Cell / Q000473:pathology*; D017154:Stromal Cells / Q000166:cytology*; D015854:Up-Regulation
D053264:B-Cell Activating Factor; C505719:TNFSF13B protein, human