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Blood, 17 September 2009, Vol. 114, No. 12, pp. 2448-2458.
Prepublished online as a Blood First Edition Paper on July 23, 2009; DOI 10.1182/blood-2008-09-181008.
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LYMPHOID NEOPLASIA
The IKK2/NF- B pathway suppresses MYC-induced lymphomagenesis
Kay Klapproth1,
Sandrine Sander1,
Dragan Marinkovic1,
Bernd Baumann1, and
Thomas Wirth1
1 Institute of Physiological Chemistry, University of Ulm, Ulm, Germany
Deregulated c-MYC is found in a variety of cancers where it promotes proliferation as well as apoptosis. In many hematologic malignancies, enhanced NF- B exerts prosurvival functions. Here we investigated the role of NF-B in mouse and human c-MYC–transformed lymphomas. The NF-B pathway is extinguished in murine lymphoma cells, and extrinsic stimuli typically inducing NF-B activity fail to activate this pathway. Genetic activation of the NF-B pathway induces apoptosis in these cells, whereas inhibition of NF-B by an IB superrepressor provides a selective advantage in vivo. Furthermore, in human Burkitt lymphoma cells we find that NF-B activation induces apoptosis. NF-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-B–induced apoptosis, and persistent inactivity of NF-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-B. Our observations provide a molecular explanation for the described absence of the NF-B signaling in Burkitt lymphoma and question the applicability of NF-B inhibitors as candidates for treatment of this cancer.
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