In continuation of earlier work of our group, we focus on the analysis of the NF-κB and AP-1 transcription factor system with respect to apoptosis resistance and proliferation. These pathways are investigated not only in HRS of cHL, but also in related lymphoma entities such as anaplastic large cell lymphoma (ALCL) and multiple myeloma.
Recent results show that overexpression of the NF-κB/IκB family member Bcl-3 constitutes a novel molecular defect of the NF-κB system in cHL and ALCL. Bcl-3 might be involved in apoptosis protection of these cells. Furthermore, we have shown that AP-1 is involved in the dedifferentiation process of HRS cells by maintaining high expression of the E2A antagonist inhibitor of differentiation 2 (Id2).
The AP-1 activity might further be enhanced by a specific overexpression of the CREB family member ATF3. ATF3 is specifically overexpressed in HRS and ALCL tumor cells and protects at least HRS cells from apoptosis. In addition, we showed that p53-dependent apoptosis can be induced in HRS cells by the MDM2-antagonist nutlin-3, and thus the activation of the p53 pathway might represent a novel treatment strategy for cHL.
These data provide insights into the deregulated apoptosis and survival signaling pathways in HRS cells.
(M. Janz, S. Mathas)