Role of active autophagy in the pathogenesis of classical Hodgkin lymphoma- leading to oncogenic transformation or tumor suppression?

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Classical Hodgkin lymphoma (cHL) is a malignant tumor of the lymphatic system that is characterized by the incidence of Hodgkin Reed-Sternberg (HRS) cells embedded in a reactive infiltrate mainly consisting of CD4+ T lymphocytes, which separates cHL from Non-Hodgkin-Lymphoma. Recent results of the group of the applicants suggest that autophagy, a cellular mechanism to degrade the own components of the cell, is activated in HRS cells. Autophagy plays a pivotal role in the pathogenesis of many solid tumors. In these tumors activated autophagy promoting tumor cell survival and progression has either been described, as well as repressed autophagy also supporting tumor pathogenesis. Little is known about the role of autophagy in the pathogenesis of lymphomas, in particular of B-cell-dependent lymphomas. In recent experiments of the group of the applicants HRS cells, as compared to germinal centre B cells and Burkitt lymphoma cells, demonstrated up-regulated expression of microtubule-associated protein 1 light chain 3 II (LC3II), a marker of activated autophagy, and an increase in the number of autophagosomes, which could be both signs of active autophagy or give evidence of defects in autophagic flux. Therefore in the planned project autophagy status will initially be analyzed by additional standard autophagy assays in HRS cells (cell lines and primary tissue) and the autophagic flux will be investigated. In the following functional experiments will be performed to investigate the importance of autophagy in the pathogenesis of Hodgkin lymphoma, that is to analyze whether the status of autophagy contributes to growth, survival and metabolic phenotype of HRS cells. If autophagy is indeed activated in HRS cells, it will be inhibited, in case of defects in autophagic flux, the flux will be induced; the effects of the induction or inhibition on cell growth, survival and metabolism will be analyzed, respectively. Furthermore, mutation analysis of important autophagy-related genes and microRNA analysis, which could both contribute to changes in the cellular status of autophagy, will be carried out. The aim of the project is to find out new mechanisms that are important in the pathogenesis of cHL to develop in the long run new therapeutic strategies.