NF-κB2 mutation targets survival, proliferation and differentiation pathways in the pathogenesis of plasma cell tumors

BMC Cancer

Research Article

William King¹  Mingqiang Ren²  Brian A McCarthy²  Jane Ding²  Han-Fei Ding²  Liqun Yang³  Mohamed Sharawy⁴  Ibrahim Zakhary⁴  Mohammed ElSalanty⁴  Hongjuan Cui⁵ 

[1] Cancer Center Genomics Core, Georgia Health Sciences University, 30912, Augusta, GA, USA;Cancer Center and Department of Pathology, Medical College of Georgia, Georgia Health Sciences University, 30912, Augusta, GA, USA;Cancer Center and Department of Pathology, Medical College of Georgia, Georgia Health Sciences University, 30912, Augusta, GA, USA;State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, College of Biotechnology, Southwest University, 400716, Chongqing, China;Department of Oral Biology, College of Dental Medicine, Georgia Health Sciences University, 30912, Augusta, GA, USA;State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, College of Biotechnology, Southwest University, 400716, Chongqing, China;

关键词: Bone Mineral Density;    Multiple Myeloma;    Plasma Cell;    Bone Marrow Plasma Cell;    Plasma Cell Tumor;   

DOI  :  10.1186/1471-2407-12-203

 received in 2011-12-02, accepted in 2012-05-29,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundAbnormal NF-κB2 activation has been implicated in the pathogenesis of multiple myeloma, a cancer of plasma cells. However, a causal role for aberrant NF-κB2 signaling in the development of plasma cell tumors has not been established. Also unclear is the molecular mechanism that drives the tumorigenic process. We investigated these questions by using a transgenic mouse model with lymphocyte-targeted expression of p80HT, a lymphoma-associated NF-κB2 mutant, and human multiple myeloma cell lines.MethodsWe conducted a detailed histopathological characterization of lymphomas developed in p80HT transgenic mice and microarray gene expression profiling of p80HT B cells with the goal of identifying genes that drive plasma cell tumor development. We further verified the significance of our findings in human multiple myeloma cell lines.ResultsApproximately 40% of p80HT mice showed elevated levels of monoclonal immunoglobulin (M-protein) in the serum and developed plasma cell tumors. Some of these mice displayed key features of human multiple myeloma with accumulation of plasma cells in the bone marrow, osteolytic bone lesions and/or diffuse osteoporosis. Gene expression profiling of B cells from M-protein-positive p80HT mice revealed aberrant expression of genes known to be important in the pathogenesis of multiple myeloma, including cyclin D1, cyclin D2, Blimp1, survivin, IL-10 and IL-15. In vitro assays demonstrated a critical role of Stat3, a key downstream component of IL-10 signaling, in the survival of human multiple myeloma cells.ConclusionsThese findings provide a mouse model for human multiple myeloma with aberrant NF-κB2 activation and suggest a molecular mechanism for NF-κB2 signaling in the pathogenesis of plasma cell tumors by coordinated regulation of plasma cell generation, proliferation and survival.

【 授权许可】

Unknown   
© McCarthy et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.