TY - JOUR
T1 - NF-κB2 mutation targets survival, proliferation and differentiation pathways in the pathogenesis of plasma cell tumors
AU - McCarthy, Brian A.
AU - Yang, Liqun
AU - Ding, Jane
AU - Ren, Mingqiang
AU - King, William
AU - Elsalanty, Mohammed Elsayed
AU - Zakhary, Ibrahim
AU - Sharawy, Mohamed M.H.
AU - Cui, Hongjuan
AU - Ding, Hanfei
N1 - Funding Information:
We are indebted to W.M. Kuehl of the National Cancer Institute for his insightful comments on the manuscript. We thank H.C. Morse of the National Institute of Allergy and Infectious Diseases, W. Gunning of the University of Toledo College of Medicine, and T. Nagy of the University of Georgia for histological examination of tumor samples. We also thank W.M. Kuehl and D. Sullivan of the Moffit Cancer Center for providing the MM cell lines EJM and H929, respectively. This work was supported by a grant from the National Cancer Institute (R01 CA106550) and Georgia Cancer Coalition Distinguished Scholar Award to HFD, and grants from and the National Basic Research Program of China (No. 2012cb114603) and the National Natural Science Foundation of China (No. 31172268) to HC. BAM is a Multiple Myeloma Research Foundation Research Fellow.
PY - 2012/5/29
Y1 - 2012/5/29
N2 - 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.
AB - 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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U2 - 10.1186/1471-2407-12-203
DO - 10.1186/1471-2407-12-203
M3 - Article
C2 - 22642622
AN - SCOPUS:84861468201
SN - 1471-2407
VL - 12
JO - BMC Cancer
JF - BMC Cancer
M1 - 203
ER -