TY - JOUR
T1 - Role of B-cell-activating factor in adhesion and growth of human multiple myeloma cells in the bone marrow microenvironment
AU - Tai, Yu-Tzu
AU - Li, Xian-Feng
AU - Breitkreutz, Iris
AU - Song, Weihua
AU - Neri, Paola
AU - Catley, Laurence
AU - Podar, Klaus
AU - Hideshima, Teru
AU - Chauhan, Dharminder
AU - Raje, Noopur
AU - Schlossman, Robert
AU - Richardson, Paul
AU - Munshi, Nikhil C
AU - Anderson, Kenneth C
PY - 2006/7/1
Y1 - 2006/7/1
N2 - Recent studies have underscored the role of B-cell-activating factor (BAFF), a member of the tumor necrosis factor superfamily, in promoting the survival of malignant B cells, including human multiple myeloma. We here characterized the functional significance of BAFF in the interaction between multiple myeloma and bone marrow stromal cells (BMSC) and further defined the molecular mechanisms regulating these processes. BAFF is detected on BMSCs derived from multiple myeloma patients as evidenced by flow cytometry. BAFF secretion is 3- to 10-fold higher in BMSCs than in multiple myeloma cells, and tumor cell adhesion to BMSCs augments BAFF secretion by 2- to 5-fold, confirmed by both ELISA and immunoblotting. Adhesion of MM1S and MCCAR multiple myeloma cell lines to KM104 BMSC line transfected with a luciferase reporter vector carrying the BAFF gene promoter (BAFF-LUC) significantly enhanced luciferase activity, suggesting that nuclear factor-κB (NF-κ) activation induced by multiple myeloma adhesion to BMSCs mediates BAFF upregulation. Moreover, BAFF (0-100 ng/mL) increases adhesion of multiple myeloma lines to BMSCs in a dose-dependent manner; conversely, transmembrane activator and calcium modulator and cyclophylin ligand interactor-Ig or B-cell maturation antigen/Fc blocked BAFF stimulation. Using adenoviruses expressing dominant-negative and constitutively expressed AKT as well as NF-κB inhibitors, we further showed that BAFF-induced multiple myeloma cell adhesion is primarily mediated via activation of AKT and NF-κB signaling. Importantly, BAFF similarly increased adhesion of CD138-expressing patient multiple myeloma cells to BMSCs. These studies establish a role for BAFF in localization and survival of multiple myeloma cells in the bone marrow microenvironment and strongly support novel therapeutics, targeting the interaction between BAFF and its receptors in human multiple myeloma.
AB - Recent studies have underscored the role of B-cell-activating factor (BAFF), a member of the tumor necrosis factor superfamily, in promoting the survival of malignant B cells, including human multiple myeloma. We here characterized the functional significance of BAFF in the interaction between multiple myeloma and bone marrow stromal cells (BMSC) and further defined the molecular mechanisms regulating these processes. BAFF is detected on BMSCs derived from multiple myeloma patients as evidenced by flow cytometry. BAFF secretion is 3- to 10-fold higher in BMSCs than in multiple myeloma cells, and tumor cell adhesion to BMSCs augments BAFF secretion by 2- to 5-fold, confirmed by both ELISA and immunoblotting. Adhesion of MM1S and MCCAR multiple myeloma cell lines to KM104 BMSC line transfected with a luciferase reporter vector carrying the BAFF gene promoter (BAFF-LUC) significantly enhanced luciferase activity, suggesting that nuclear factor-κB (NF-κ) activation induced by multiple myeloma adhesion to BMSCs mediates BAFF upregulation. Moreover, BAFF (0-100 ng/mL) increases adhesion of multiple myeloma lines to BMSCs in a dose-dependent manner; conversely, transmembrane activator and calcium modulator and cyclophylin ligand interactor-Ig or B-cell maturation antigen/Fc blocked BAFF stimulation. Using adenoviruses expressing dominant-negative and constitutively expressed AKT as well as NF-κB inhibitors, we further showed that BAFF-induced multiple myeloma cell adhesion is primarily mediated via activation of AKT and NF-κB signaling. Importantly, BAFF similarly increased adhesion of CD138-expressing patient multiple myeloma cells to BMSCs. These studies establish a role for BAFF in localization and survival of multiple myeloma cells in the bone marrow microenvironment and strongly support novel therapeutics, targeting the interaction between BAFF and its receptors in human multiple myeloma.
KW - B-Cell Activating Factor
KW - Bone Marrow Cells/metabolism
KW - Bone Marrow Neoplasms/metabolism
KW - Cell Adhesion/physiology
KW - Cell Growth Processes/physiology
KW - Cell Line, Tumor
KW - Humans
KW - Membrane Proteins/biosynthesis
KW - Multiple Myeloma/metabolism
KW - NF-kappa B/metabolism
KW - Proto-Oncogene Proteins c-akt/metabolism
KW - Receptors, Interleukin-4/biosynthesis
KW - Signal Transduction
KW - Stromal Cells/metabolism
KW - Tumor Necrosis Factor-alpha/biosynthesis
UR - http://www.scopus.com/inward/record.url?scp=33746122751&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-06-0190
DO - 10.1158/0008-5472.CAN-06-0190
M3 - Journal article
C2 - 16818641
SN - 0008-5472
VL - 66
SP - 6675
EP - 6682
JO - Cancer Research
JF - Cancer Research
IS - 13
ER -