The pathogenetic significance of deregulated signal transduction pathways in Hodgkin's disease: the NF-kappaB-AP-1 network.

In the recent years, progress has been made in defining the lineage origin of malignant cells of Hodgkin's disease. The use of single cell PCR analysis and of other molecular probes has allowed to determine that the malignant Hodgkin/Reed-Sternberg cells correspond mostly to a post germinal center stage of normal B-lymphocyte development. However, the agents which cause primary transformation events are still unknown. A comprehensive analysis of dysregulated signaling pathways in H/RS-cells with a focus on inducible and lymphoid-specific transcription factors has provided an independent approach to characterize molecular lesions, which may account for the tumorigenicity of H/RS-cells. Transcription factors of the NF-kappaB and AP-1 multigene families could be identified as crucial mediators of both, cell cycle promoting and cell-death inhibiting pathways in H/RS-cells. High level activity of these regulators has multifarious consequences for the gene expression repertoire of H/RS-cells, as has been revealed by large scale gene profiling. The dissection of the molecular mechanisms which constitutively activate NF-kappaB and AP-1 may help to gain further insight into the pathogenesis of Hodgkin's disease and may provide novel targets for pharmacological intervention.