NF-κB2 mutation targets survival, proliferation and differentiation pathways in the pathogenesis of plasma cell tumors.
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.
Cancer Center and Department of Pathology, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, USA.
Brian A
BA
McCarthy
Liqun
L
Yang
Jane
J
Ding
Mingqiang
M
Ren
William
W
King
Mohammed
M
ElSalanty
Ibrahim
I
Zakhary
Mohamed
M
Sharawy
Hongjuan
H
Cui
Han-Fei
HF
Ding
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D052003:NF-kappa B p52 Subunit / Q000235:genetics* / Q000378:metabolism; D010954:Plasmacytoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D001798:Blood Proteins; D052003:NF-kappa B p52 Subunit; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha