Mantle cell lymphoma (MCL) is a non-Hodgkin's lymphoma that remains incurable due to the development of drug resistance, which is typically marked by unrestrained tumor cell proliferation. Cell cycle dysregulation is a hallmark of MCL. In particular, overexpression of CDK4, together with aberrant cyclin D1 expression, drives unrestrained proliferation of tumor cells that underlies disease progression and expansion of resistant clones. However, the molecular basis for drug resistance in MCL remains obscure. The overall goals of the program project are: 1) to develop superior, mechanism-based combination therapies that both control tumor expansion and enhance tumor killing in MCL, 2) to elucidate the mechanism(s) of drug resistance, and 3) to advance genome-based patient and therapy stratification for optimal and durable clinical responses. To achieve these goals, a team of investigators with strong, complementary expertise in basic science, cancer research, experimental therapeutics and patient care at Weill Cornell Medicine (WCM) and The Ohio State University OSU) have assembled three interactive projects to 1) target CDK4 in MCL therapy; 2) to elucidate the role of FOXO and chromatin remodeling in cell cycle therapy for MCL; and 3) to target PRMT5 in MCL. These projects are supported by four outstanding Cores: 1) Administrative Core, 2) Pathology Core; 3) Genomics and Bioinformatics Core; and 4) Biostatistics Core. The projects and cores are highly integrated at both the conceptual and technical levels, with ideas and unpublished data shared freely on a real-time basis. The PPG, led by the Principal Investigator, will hold scheduled bi-weekly meetings via video conferencing in addition to impromptu discussions, both face-to-face or via teleconferences and frequent phone calls and emails. The chain of authority for decision-making and administration rests with the Principal Investigator, in consultation with individual Project and Core leaders. The PPG is supported by an External Advisory Board composed of four distinguished investigators who will participate in the annual review meeting in which progress and plans for each Project and Core are presented for discussion and review. The PPG is further supported by Internal Advisory Boards at WCM and OSU, who are available as needed for consultation, either singly or as a panel. Synergy among Investigators, as well as between WCM and OSU, is the most outstanding feature of this PPG and will propel its progress.