title: APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment.
abstract: Here we show that overexpression or activation of B-cell maturation antigen (BCMA) by its ligand, a proliferation-inducing ligand (APRIL), promotes human multiple myeloma (MM) progression in vivo. BCMA downregulation strongly decreases viability and MM colony formation; conversely, BCMA overexpression augments MM cell growth and survival via induction of protein kinase B (AKT), MAPK, and nuclear factor (NF)-κB signaling cascades. Importantly, BCMA promotes in vivo growth of xenografted MM cells harboring p53 mutation in mice. BCMA-overexpressing tumors exhibit significantly increased CD31/microvessel density and vascular endothelial growth factor compared with paired control tumors. These tumors also express increased transcripts crucial for osteoclast activation, adhesion, and angiogenesis/metastasis, as well as genes mediating immune inhibition including programmed death ligand 1, transforming growth factor β, and interleukin 10. These target genes are consistently induced by paracrine APRIL binding to BCMA on MM cells, which is blocked by an antagonistic anti-APRIL monoclonal antibody hAPRIL01A (01A). 01A is cytotoxic against MM cells even in the presence of protective bone marrow (BM) myeloid cells including osteoclasts, macrophages, and plasmacytoid dendritic cells. 01A further decreases APRIL-induced adhesion and migration of MM cells via blockade of canonical and noncanonical NF-κB pathways. Moreover, 01A prevents in vivo MM cell growth within implanted human bone chips in SCID mice. Finally, the effect of 01A on MM cell viability is enhanced by lenalidomide and bortezomib. Taken together, these data delineate new molecular mechanisms of in vivo MM growth and immunosuppression critically dependent on BCMA and APRIL in the BM microenvironment, further supporting targeting this prominent pathway in MM.
authors.affiliation: The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA;
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.affiliation: The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Chirag
authors.initials: C
authors.lastname: Acharya
authors.affiliation: The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Gang
authors.initials: G
authors.lastname: An
authors.affiliation: The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Michele
authors.initials: M
authors.lastname: Moschetta
authors.affiliation: The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Mike Y
authors.initials: MY
authors.lastname: Zhong
authors.affiliation: The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Feng
authors.affiliation: The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Michele
authors.initials: M
authors.lastname: Cea
authors.affiliation: The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Antonia
authors.initials: A
authors.lastname: Cagnetta
authors.affiliation: The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA;
authors.forename: Kenneth
authors.initials: K
authors.lastname: Wen
authors.affiliation: Aduro Biotech Europe (formerly known as BioNovion), Oss, The Netherlands; and.
authors.forename: Hans
authors.initials: H
authors.lastname: van Eenennaam
authors.affiliation: Aduro Biotech Europe (formerly known as BioNovion), Oss, The Netherlands; and.
authors.forename: Andrea
authors.initials: A
authors.lastname: van Elsas
authors.affiliation: Department of Lymphoma & Myeloma, Tianjin Cord Blood Bank, Institute of Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
authors.forename: Lugui
authors.initials: L
authors.lastname: Qiu
authors.affiliation: The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA;
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.affiliation: The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA;
authors.forename: Nikhil
authors.initials: N
authors.lastname: Munshi
authors.affiliation: The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA;
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000818:Animals; D053301:B-Cell Maturation Antigen / Q000235:genetics / Q000502:physiology*; D001853:Bone Marrow / Q000473:pathology / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D060833:Cellular Microenvironment / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics*; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000235:genetics / Q000473:pathology*; D010010:Osteoclasts / Q000473:pathology / Q000502:physiology; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000502:physiology*
chemical_list: D053301:B-Cell Maturation Antigen; C086966:TNFRSF17 protein, human; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13