Collectively, lymphomas (also known as Hodgkin and Non-Hodgkin lymphomas) are the 4th most common cancers in men and women and affect patients of all ages. Lymphomas are very diverse in their biology and clinical behaviour, and are therefore heavily sub-divided to guide treating physicians and patients in their choice of the best available therapy. However, the current standard of care fails to eliminate the lymphoma in a substantial proportion of patients who are then very likely to succumb to their disease. Unfortunately, the causes for these unfavorable clinical courses are mostly unknown. With this proposal we aim to significantly improve the survival for patients with a specific type of lymphoma, called primary mediastinal large B cell lymphoma (PMBCL). PMBCL often affects young patients in their third or fourth decade of life. Earlier studies by our group discovered genetic changes involved in PMBCL tumour cell signaling and tumor growth ("JAK-STAT signaling"). However, we do not understand how these identified gene mutations contribute to cancer development. Further, it is unclear how the knowledge about JAK-STAT signaling can be used to improve therapies for affected patients. We propose to use tumor tissue from lymphoma patients to characterize the mutations and the resulting clinical courses in more detail and to study the consequences of the mutations in cell culture and animal models of PMBCL. We will also use these model systems to identify changes in the tumour cells that can be targeted by drug candidates. These investigations are needed before clinical trials using these drugs can be conducted in patients. We hope that our studies will enable treating physicians to deliver "personalized treatments" to lymphoma patients; maximizing cure rates and minimizing treatment-related side effects.