title: Role of B-cell-activating factor in adhesion and growth of human multiple myeloma cells in the bone marrow microenvironment.
abstract: 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-kappaB (NF-kappaB) 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-kappaB inhibitors, we further showed that BAFF-induced multiple myeloma cell adhesion is primarily mediated via activation of AKT and NF-kappaB 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.
authors.affiliation: The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA. yu-tzu_tai@dfci.harvard.edu
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.forename: Xian-Feng
authors.initials: XF
authors.lastname: Li
authors.forename: Iris
authors.initials: I
authors.lastname: Breitkreutz
authors.forename: Weihua
authors.initials: W
authors.lastname: Song
authors.forename: Paola
authors.initials: P
authors.lastname: Neri
authors.forename: Laurence
authors.initials: L
authors.lastname: Catley
authors.forename: Klaus
authors.initials: K
authors.lastname: Podar
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.forename: Noopur
authors.initials: N
authors.lastname: Raje
authors.forename: Robert
authors.initials: R
authors.lastname: Schlossman
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D053264:B-Cell Activating Factor; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D019046:Bone Marrow Neoplasms / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000096:biosynthesis; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*
chemical_list: D053264:B-Cell Activating Factor; D008565:Membrane Proteins; D016328:NF-kappa B; D019948:Receptors, Interleukin-4; C505719:TNFSF13B protein, human; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt