The IKK2/NF-kappa B pathway suppresses MYC-induced lymphomagenesis

Abstract

Deregulated c-MYC is found in a variety of cancers where it promotes proliferation as well as apoptosis. In many hematologic malignancies, enhanced NF-kappa B exerts prosurvival functions. Here we investigated the role of NF-kappa B in mouse and human c-MYC-transformed lymphomas. The NF-kappa B pathway is extinguished in murine lymphoma cells, and extrinsic stimuli typically inducing NF-kappa B activity fail to activate this pathway. Genetic activation of the NF-kappa B pathway induces apoptosis in these cells, whereas inhibition of NF-kappa B by an I kappa B alpha superrepressor provides a selective advantage in vivo. Furthermore, in human Burkitt lymphoma cells we find that NF-kappa B activation induces apoptosis. NF-kappa B up-regulates Fas and predisposes to Fas-induced cell death, which is caspase-8 mediated and can be prevented by CFLAR overexpression. We conclude that c-MYC overexpression sensitizes cells to NF-kappa B-induced apoptosis, and persistent inactivity of NF-kappa B signaling is a prerequisite for MYC-mediated tumorigenesis. We could also show that low immunogenicity and Fas insensitivity of MYC-driven lymphoma cells are reversed by activation of NF-kappa B. Our observations provide a molecular explanation for the described absence of the NF-kappa B signaling in Burkitt lymphoma and question the applicability of NF-kappa B inhibitors as candidates for treatment of this cancer. (Blood. 2009; 114: 2448-2458)