title: Opposing roles of NF-κB in anti-cancer treatment outcome unveiled by cross-species investigations.
abstract: In malignancies, enhanced nuclear factor-κB (NF-κB) activity is largely viewed as an oncogenic property that also confers resistance to chemotherapy. Recently, NF-κB has been postulated to participate in a senescence-associated and possibly senescence-reinforcing cytokine response, thereby suggesting a tumor-restraining role for NF-κB. 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-κB signaling, whereas NF-κB simultaneously promotes resistance to apoptosis. Further characterization and genetic engineering of primary mouse lymphomas according to distinct NF-κB-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.
authors: Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors: Hua
authors: H
authors: Jing
authors: Julia
authors: J
authors: Kase
authors: Jan R
authors: JR
authors: Dörr
authors: Maja
authors: M
authors: Milanovic
authors: Dido
authors: D
authors: Lenze
authors: Michael
authors: M
authors: Grau
authors: Gregor
authors: G
authors: Beuster
authors: Sujuan
authors: S
authors: Ji
authors: Maurice
authors: M
authors: Reimann
authors: Peter
authors: P
authors: Lenz
authors: Michael
authors: M
authors: Hummel
authors: Bernd
authors: B
authors: Dörken
authors: Georg
authors: G
authors: Lenz
authors: Claus
authors: C
authors: Scheidereit
authors: Clemens A
authors: CA
authors: Schmitt
authors: Soyoung
authors: S
authors: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects* / Q000502:physiology*; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B