Abstract
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.
Highlights
Abnormal NF-κB2 activation has been implicated in the pathogenesis of multiple myeloma, a cancer of plasma cells
Sustained NF-κB2 activation can be caused by chromosomal translocations and rearrangements at the NF-κB2 locus, which occur in a variety of lymphoid malignancies including T-cell lymphoma, chronic lymphocytic leukemia, multiple myeloma, and B-cell lymphoma [5]
Gene expression profiling of B cells from p80HT mice To gain a molecular understanding into the oncogenic activity of p80HT in plasma cell tumor development, we examined the gene expression profile of B cells isolated from 1-year-old p80HT mice that were positive for serum M-protein and from their wild-type littermates (n = 3 per genotype)
Summary
Abnormal NF-κB2 activation has been implicated in the pathogenesis of multiple myeloma, a cancer of plasma cells. 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. To determine whether NF-κB2 mutation can directly initiate lymphomagenesis, we have generated transgenic mice with targeted expression in lymphocytes of p80HT, a lymphomaassociated NF-κB2 mutant [11,12]. These transgenic mice develop predominantly B-cell tumors, demonstrating that NF-κB2 mutations can have a causal role in lymphomagenesis [13]
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