Investigation of the function of the IKK2/NF-kappaB-pathway in c-MYC-induced lymphomagenesis
Klapproth, Kay Oliver
FacultiesFakultät für Naturwissenschaften
LicenseStandard (Fassung vom 01.10.2008)
Prosurvival activity of NF-kappaB is essential for many hematological malignancies like Hodgkins lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), mucosa associated lymphoid tissue (MALT) lymphoma, multiple myeloma (MM) and many others. For Burkitts lymphoma (BL), a malignancy caused by overexpressed MYC in B-cells, the contribution of the NF-kappaB pathway for growth and survival of the tumor cells remained elusive. In the present study it could be demonstrated that in MYC-driven murine B-cell lymphomas and human BL the activation of NF-kappaB is impaired. In lymphoma cell lines established from a conditional c-MYC expressing mouse model it was shown that the NF-kappaB pathway is dispensable for tumor growth and generally downregulated. Furthermore, several extrinsic stimuli generally inducing NF-kappaB activity failed to activate this pathway. In addition, inhibition of NF-kappaB by an IkappaBalpha superrepressor provided a selective advantage for MYC-driven lymphoma cells in an in vivo competition assay. Genetic activation of the NF-kappaB pathway by introduction of a constitutively active IkappaB-kinase 2 (IKK2) induced cell aggregation, growth inhibition and apoptosis in MYC-driven lymphomas. Extending our analysis to human BL cell lines we found that NF-kappaB activation induced similar effects by enhancing cell aggregation and apoptosis. The induced cell death was death receptor-mediated and specific for BL cells. Gene expression profiling revealed that induction of IKK2 activity resulted in prominent upregulation of cell adhesion molecules and Fas death receptor. Subsequently, it could be demonstrated that Fas-resistant BL cell lines are sensitized to Fas-mediated death by NF-kappaB activation.
Subject HeadingsMyc [GND]
Nuklearfaktor Kappa B [GND]
B cells [LCSH]