Epigenetics in NPM-ALK Positive Lymphomas

Non-Hodgkin`s lymphomas (NHL) are a rising group of malignant tumors, with more than 800 new cases in Austria per year. Anaplastic large cell lymphoma (ALCL), a highly malignant T cell NHL, is frequently associated with a genetic translocation generating the NPM-ALK fusion protein. The fusion is highly oncogenic in vitro and in vivo and has been shown to interact with a variety of oncogenic networks. Besides genetic mutations, epigenetic aberrations have been associated with numerous tumors. Silencing of tumor suppressor genes by DNA methylation was shown to be a hallmark of human cancer. A second epigenetic pathway is dependent on the action of Polycomb proteins, which can act as oncogenes. Interestingly, only a limited amount of literature exists on the involvement of epigenetic mechanisms in ALCL. Here we propose to analyze the role of epigenetics on the development and progression of NPM-ALK positive lymphomas. We plan to use an integrated approach to study changes in DNA methylation and Polycomb occupancy in human tumor samples, cell lines and in a transgenic mouse model. We will use human tissue arrays to determine the expression status of Polycomb proteins in several NPM-ALK positive and negative lymphoma patient samples. Custom tiling arrays will be used to determine the epigenetic profile of different ALCL cell lines. Furthermore, we plan to use NPM-ALK transgenic mice to elucidate the role of DNA methylation and Polycomb proteins in murine lymphomagenesis and to isolate putative novel targets of epigenetic aberrations. To investigate the biological importance of these aberrations, we will treat human cell lines with specific epigenetic drugs. We will intercross mice with a T-cell specific deletion of Dnmt1 with NPM-ALK transgenic mice to study the effects of DNA hypomethylation on NPM-ALK dependent tumor-formation and - progression. The use of epigenetic drugs, such as DNA methyltransferase inhibitors and histone deacetylase inhibitors has been approved by the US food and drug administration for the treatment of specific hematological malignancies, and clinical trials have shown the beneficial effects for several tumor types of tumors. Thus, our study may elucidate novel molecular mechanisms of the disease and provide a rationale for the application of epigenetic drugs to target ALCL.