Title: Targeting of the developmental blockade in extranodal natural killer/T cell lymphoma Extranodal natural killer/T cell lymphoma (ENKTL) is a highly aggressive lymphoma that usually afflicts those of far Eastern Asian and Central/South American heritage. Despite the use of intensive chemotherapy treatments most patients succumb to the disease, highlighting the critical need to develop better and safer therapies. Due to the rarity of ENKTL, less is known about the biology of disease including the cause, the cells that give rise to the cancer, and the key cellular events and processes that cause the tumor cells to survive and grow uncontrollably. In our preliminary studies, we have identified the likely source of normal cells that give rise to ENKTL tumor cells, allowing us to make detailed comparisons of the biology of the tumor cells. Cells develop normally from immature precursor cells, and we have importantly found that ENKTL cells are locked into specific stages of immature cell development. We have discovered that ENKTL cells exhibit a DNA abnormality called hypermethylation that is likely responsible for the developmental blockage. We believe that this DNA abnormality could represent the cancer’s “Achilles’ heel” and can be targeted with current FDA approved drugs termed hypomethylating agents that are known to affect this defect. We next developed a novel way to model ENKTL in mice using patient-derived tumor cells. Using this model, we have discovered that use of hypomethylating agents is highly effective in eliminating tumor cells, leading to a cure in some mice. However some resistance to the therapy is observed. Partnering with a large international collaborative group including researchers from ENKTL endemic regions Peru, Guatemala and Taiwan, as well as several institutions here in the United States, my laboratory will determine how prevalent this DNA abnormality is across a range of patient populations and if DNA hypermethylation is a promising target for treatment. We will also look for potential other features of tumor cells that contribute to or synergize with hypermethylation, and if the degree of hypermethylation and development blockage is a useful biomarker that could be used in disease prognosis. We have also uncovered a potential cause of hypermethylation that relates to novel biology surrounding viral infection of tumor cells. We will test the role of this potential mechanism in normal and tumor cells. Using our novel disease models, we will investigate how hypomethylating agents kill cancer cells and how surviving cells evade the therapy. We also will use our systems to devise improved ways to build on hypomethylating agents to more effectively kill cells and circumvent resistance. At the completion of this project we will have gained a better understanding of the origins, causes and utility of the underlying fundamental features of ENKTL. We hope to provide a foundation for a new therapy for patients in need of a better and safer treatment for this devastating disease.