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Opposing roles of NF-{kappa}B in anti-cancer treatment outcome unveiled by cross-species investigations

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Official URL:https://doi.org/10.1101/gad.17620611
PubMed:View item in PubMed
Creators Name:Jing, H. and Kase, J. and Doerr, J.R. and Milanovic, M. and Lenze, D. and Grau, M. and Beuster, G. and Ji, S. and Reimann, M. and Lenz, P. and Hummel, M. and Doerken, B. and Lenz, G. and Scheidereit, C. and Schmitt, C.A. and Lee, S.
Journal Title:Genes & Development
Journal Abbreviation:Genes Dev
Volume:25
Number:20
Page Range:2137-2146
Date:15 October 2011
Keywords:Cancer Therapy, Cellular Senescence, DLBCL, Lymphoma, Mouse Models, NF-{kappa}B, Antineoplastic Agents, Cell Aging, Tumor Cell Line, Cell Survival, Neoplastic Gene Expression Regulation, B-Cell Lymphoma, Large B-Cell Lymphoma, Non-Hodgkin Lymphoma, NF-kappa B, Signal Transduction, Animals, Mice
Abstract:In malignancies, enhanced nuclear factor-{kappa}B (NF-{kappa}B) activity is largely viewed as an oncogenic property that also confers resistance to chemotherapy. Recently, NF-{kappa}B has been postulated to participate in a senescence-associated and possibly senescence-reinforcing cytokine response, thereby suggesting a tumor-restraining role for NF-{kappa}B. Using a mouse lymphoma model and analyzing transcriptome and clinical data from lymphoma patients, we show here that therapy-induced senescence presents with and depends on active NF-{kappa}B signaling, whereas NF-{kappa}B simultaneously promotes resistance to apoptosis. Further characterization and genetic engineering of primary mouse lymphomas according to distinct NF-{kappa}B-related oncogenic networks reminiscent of diffuse large B-cell lymphoma (DLBCL) subtypes guided us to identify Bcl2-overexpressing germinal center B-cell-like (GCB) DLBCL as a clinically relevant subgroup with significantly superior outcome when NF-κB is hyperactive. Our data illustrate the power of cross-species investigations to functionally test genetic mechanisms in transgenic mouse tumors that recapitulate distinct features of the corresponding human entity, and to ultimately use the mouse model-derived genetic information to redefine novel, clinically relevant patient subcohorts.
ISSN:0890-9369
Publisher:Cold Spring Harbor Laboratory Press (U.S.A.)
Item Type:Article

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