Role of B-cell-activating factor in adhesion and growth of human multiple myeloma cells in the bone marrow microenvironment

被引：186

作者：

Tai, Yu-Tzu ^{[1
]}

Li, Xian-Feng ^{[1
]}

Breitkreutz, Iris ^{[1
]}

Song, Weihua ^{[1
]}

Neri, Paola ^{[1
]}

Catley, Laurence ^{[1
]}

Podar, Klaus ^{[1
]}

Hideshima, Tern ^{[1
]}

Chauhan, Dharminder ^{[1
]}

Raje, Noopur ^{[1
]}

Schlossman, Robert ^{[1
]}

Richardson, Paul ^{[1
]}

Munshi, Nikhil C. ^{[1
]}

Anderson, Kenneth C. ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr,Dept Med Oncol, Boston, MA 02215 USA

来源：

CANCER RESEARCH | 2006年 / 66卷 / 13期

关键词：

D O I：

10.1158/0008-5472.CAN-06-0190

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. RAFF 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 MMIS 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-kappa B (NF-kappa B) activation induced by multiple myeloma adhesion to BMSCs mediates BAFF up-regulation. 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-kappa B inhibitors, we further showed that BAFF-induced multiple myeloma cell adhesion is primarily mediated via activation of AKT and NF-kappa B 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 mycloma cells in the bone marrow microenvironment and strongly support novel therapeutics, targeting the interaction between BAFF and its receptors in human multiple myeloma.

引用

页码：6675 / 6682

页数：8

共 40 条

[1] Graft-versus-tumor response in patients with multiple myeloma is associated with antibody response to BCMA, a plasma-cell membrane receptor [J].