NF-kB2 mutation targets survival, proliferation and differentiation pathways in the pathogenesis of plasma cell tumors

Hdl Handle:
http://hdl.handle.net/10675.2/723
Title:
NF-kB2 mutation targets survival, proliferation and differentiation pathways in the pathogenesis of plasma cell tumors
Authors:
McCarthy, Brian A.; Yang, Liqun; Ding, Jane; Ren, MingQiang; King, William; ElSalanty, Mohammed; Zakhary, Ibrahim; Sharawy, Mohamed; Cui, Hongjuan; Ding, Han-Fei ( 0000-0001-5702-3439 )
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.
Citation:
BMC Cancer. 2012 May 29; 12:203
Issue Date:
29-May-2012
URI:
http://hdl.handle.net/10675.2/723
DOI:
10.1186/1471-2407-12-203
PubMed ID:
22642622
PubMed Central ID:
PMC3407530
Type:
Article
ISSN:
1471-2407
Appears in Collections:
Georgia Cancer Center: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorMcCarthy, Brian A.en_US
dc.contributor.authorYang, Liqunen_US
dc.contributor.authorDing, Janeen_US
dc.contributor.authorRen, MingQiangen_US
dc.contributor.authorKing, Williamen_US
dc.contributor.authorElSalanty, Mohammeden_US
dc.contributor.authorZakhary, Ibrahimen_US
dc.contributor.authorSharawy, Mohameden_US
dc.contributor.authorCui, Hongjuanen_US
dc.contributor.authorDing, Han-Feien_US
dc.date.accessioned2012-10-26T16:40:53Z-
dc.date.available2012-10-26T16:40:53Z-
dc.date.issued2012-05-29en_US
dc.identifier.citationBMC Cancer. 2012 May 29; 12:203en_US
dc.identifier.issn1471-2407en_US
dc.identifier.pmid22642622en_US
dc.identifier.doi10.1186/1471-2407-12-203en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/723-
dc.description.abstractBackground: 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.en_US
dc.description.abstractMethods: 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.en_US
dc.description.abstractResults: 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.en_US
dc.description.abstractConclusions: 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.en_US
dc.rightsCopyright ©2012 McCarthy et al.; licensee BioMed Central Ltd.en_US
dc.subjectResearch Articleen_US
dc.titleNF-kB2 mutation targets survival, proliferation and differentiation pathways in the pathogenesis of plasma cell tumorsen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC3407530en_US
dc.contributor.corporatenameGHSU Cancer Center-
dc.contributor.corporatenameDepartment of Pathology-
dc.contributor.corporatenameDepartment of Oral Biology-

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