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

  1. Soyoung Lee2
  1. 1Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany;
  2. 2Department of Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin, Campus Virchow Clinic, Molekulares Krebsforschungszentrum, D-13353 Berlin, Germany;
  3. 3Department of Pathology, Charité-Universitätsmedizin, D-10117 Berlin, Germany;
  4. 4Department of Physics, Philipps-University Marburg, D-35032 Marburg, Germany
    1. 5 These authors contributed equally to this work.

    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.

    Keywords

    Footnotes

    • Received August 4, 2011.
    • Accepted September 6, 2011.
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