Opposing roles of NF-κB in anti-cancer treatment outcome unveiled by cross-species investigations
Authors
- H. Jing
- J. Kase
- J.R. Dörr
- M. Milanovic
- D. Lenze
- M. Grau
- G. Beuster
- S. Ji
- M. Reimann
- P. Lenz
- M. Hummel
- B. Doerken
- G. Lenz
- C. Scheidereit
- C.A. Schmitt
- S. Lee
Journal
- Genes & Development
Citation
- Genes Dev 25 (20): 2137-2146
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.