APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment
| Autor: | Michele Moschetta, Paul G. Richardson, Xiaoyan Feng, Michele Cea, Mike Y Zhong, Antonia Cagnetta, Lugui Qiu, Yu-Tzu Tai, Nikhil C. Munshi, Kenneth Wen, Kenneth C. Anderson, Hans van Eenennaam, Andrea van Elsas, Gang An, Chirag Acharya |
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| Rok vydání: | 2016 |
| Předmět: |
Angiogenesis
Immunology Tumor Necrosis Factor Ligand Superfamily Member 13 Osteoclasts Mice SCID Biology Biochemistry 03 medical and health sciences Paracrine signalling Mice 0302 clinical medicine Osteoclast Bone Marrow Cell Line Tumor medicine Immune Tolerance Cytotoxic T cell Animals Humans B-Cell Maturation Antigen Cell Proliferation Lymphoid Neoplasia Cell growth Cell Biology Hematology Gene Expression Regulation Neoplastic Vascular endothelial growth factor A medicine.anatomical_structure Cellular Microenvironment 030220 oncology & carcinogenesis Cancer research Heterografts Bone marrow Multiple Myeloma 030215 immunology Transforming growth factor |
| Zdroj: | Blood. 127(25) |
| ISSN: | 1528-0020 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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