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Opposing roles of NF-κB in anti-cancer treatment outcome unveiled by cross-species investigations

Authors

  • H. Jing
  • J. Kase
  • J.R. Doerr
  • 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.


DOI

doi:10.1101/gad.17620611