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BMC Cancer. 2012; 12: 203.
Published online May 29, 2012. doi:  10.1186/1471-2407-12-203
PMCID: PMC3407530
NF-κB2 mutation targets survival, proliferation and differentiation pathways in the pathogenesis of plasma cell tumors
Brian A McCarthy,#1 Liqun Yang,#1,4 Jane Ding,1 Mingqiang Ren,1 William King,2 Mohammed ElSalanty,3 Ibrahim Zakhary,3 Mohamed Sharawy,3 Hongjuan Cui,corresponding author4 and Han-Fei Dingcorresponding author1
1Cancer Center and Department of Pathology, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA, 30912, USA
2Cancer Center Genomics Core, Georgia Health Sciences University, Augusta, GA, 30912, USA
3Department of Oral Biology, College of Dental Medicine, Georgia Health Sciences University, Augusta, GA, 30912, USA
4State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, College of Biotechnology, Southwest University, Chongqing, 400716, China
corresponding authorCorresponding author.
#Contributed equally.
Brian A McCarthy: bmc333/at/gmail.com; Liqun Yang: lyang/at/georgiahealth.edu; Jane Ding: jding/at/georgiahealth.edu; Mingqiang Ren: mren/at/georgiahealth.edu; William King: clking/at/georgiahealth.edu; Mohammed ElSalanty: melsalanty/at/georgiahealth.edu; Ibrahim Zakhary: izakhary/at/georgiahealth.edu; Mohamed Sharawy: msharawy/at/georgiahealth.edu; Hongjuan Cui: hongjuan.cui/at/gmail.com; Han-Fei Ding: hding/at/georgiahealth.edu
Received December 2, 2011; Accepted May 29, 2012.
Abstract
Background
Abnormal 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.
Methods
We 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.
Results
Approximately 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.
Conclusions
These 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.
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