Onkogenomische Aspekte Zytokin-assoziierter Signaltransduktion

Abstract

In lymphoma patients current therapeutic regimen are associated with a high toxic burden as well as the development of therapy-associated secondary malignancies. Moreover, risk factors influencing these diseases are currently not well defined. To improve the therapy of lymphoma patients, biological factors have to be characterised, which influence the lymphoma disease and could act as therapeutic targets. The aim of this study was to analyse cytokines and the respective signal transduction via the Jak-STAT pathway with regard to these aspects. The first part of this study provides evidence that Janus kinases are permanently activated in classical Hodgkin Lymphoma (cHL) cell lines. Likewise, it could be shown that inhibition of chaperone HSP90 by geldanamycin derivative 17-AAG or RNA interference against HSP90 leads to an inhibition of the Jak-STAT signaling pathway accompanied by a reduced proliferation of cHL cells. In the second part of this study the targets of the transcription factor STAT6 were analysed using gene expression profiling after RNA interference of STAT6 in cHL cells. These results were in part validated and included genes like the transcription factor IRF4, the Interleukin 13 receptor IL13Ra1, the receptor tyrosine kinase EphB1 and the protein phosphatase PTPRK. These factors could be associated with the malignant phenotype of cHL cells and may represent targets for new therapeutic intervention possibilities. In the third part of this study an association of inherited gene variations of cytokines and cytokine receptors with the clinical course of lymphoma patients was demonstrated. A correlation was found between NHL patients homozygous for the distal IL-10 promotor gene variation IL-10-7400Del and a worse clinical outcome. In a cohort of DLBCL patients a better clinical course was demonstrated for patients with a IL-4 receptor allelic variant. Further studies have to prove if these gene variations could become prognostic factors in addition to the current factors of the International Prognostic Index (IPI). In conclusion this study underlines the importance of cytokines and their respective signal transduction with regard to the development of new therapeutic strategies and to the risk stratification of lymphoma patients.