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

经典霍奇金淋巴瘤（cHL）是淋巴系统的恶性肿瘤，其特征在于霍奇金Reed-Sternberg（HRS）细胞包埋在主要由CD 4 + T淋巴细胞组成的反应性浸润中，将cHL与非霍奇金淋巴瘤区分开来。本申请人小组的最近结果表明，自噬（降解细胞自身组分的细胞机制）在HRS细胞中被激活。自噬在许多实体瘤的发病机制中起着关键作用。在这些肿瘤中，已经描述了促进肿瘤细胞存活和进展的活化的自噬，以及也支持肿瘤发病机制的抑制的自噬。关于自噬在淋巴瘤，特别是B细胞依赖性淋巴瘤的发病机制中的作用知之甚少。在本申请人的组的最近实验中，与生发中心B细胞和伯基特淋巴瘤细胞相比，HRS细胞显示微管相关蛋白1轻链3 II（LC 3 II）（活化的自噬的标志物）的表达上调，以及自噬体数量的增加，这可能是活性自噬的迹象或提供自噬通量缺陷的证据。因此，在计划的项目中，首先将通过HRS细胞（细胞系和原代组织）中的额外标准自噬测定来分析自噬状态，并将研究自噬通量。本研究将通过功能实验探讨自噬在霍奇金淋巴瘤发病机制中的重要性，即分析自噬状态是否对HRS细胞的生长、存活和代谢表型有影响。如果自噬在HRS细胞中确实被激活，则其将被抑制，在自噬通量缺陷的情况下，将诱导该通量;将分别分析诱导或抑制对细胞生长、存活和代谢的影响。此外，还将进行重要的自噬相关基因的突变分析和microRNA分析，这两者都可能有助于自噬细胞状态的变化。该项目的目的是找出cHL发病机制中重要的新机制，以开发长期新的治疗策略。

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.