The long-term goal of the Lymphoid Development and Malignancy (LDM) Program is to improve outcomes and seek cures for patients with lymphoid malignancies, including acute lymphoblastic leukemia (ALL) and B cell non-Hodgkin lymphoma (B-NHL). The Program is motivated by the notion that new therapeutic modalities of high efficacy and low toxicity can be developed by specifically targeting the altered oncogenic pathways of malignant cells. To achieve this end, the following Specific Goals will be pursued: 1) identify major cellular pathways that regulate the development of lymphoid tissues. Molecular biology, genetic and systems biology approaches will be used to elucidate cellular pathways that regulate the growth, survival and differentiation of immature lymphocytes (the precursors of ALL) and mature B cells (the precursors of BNHL); 2) Identify genes and pathways involved in the pathogenesis of lymphoid malignancies. In particular, the genetic lesions and deregulated cellular pathways that are casually associated with the pathogenesis of ALL and B-NHL will be identified; 3) Develop novel therapies that target the deregulated cellular pathways of lymphoid malignancies. Known drugs as well as compounds identified through screening approaches will be tested as single agents and in combinations for their ability to target deregulated pathways in lymphoid malignancies using pre-clinical models and Phase l/ll clinical trials. The LDM Program consists of 35 members (22 full) from 4 Columbia University Departments (Medicine, Microbiology, Pathology and Pediatrics). The Program hosts several multi-PI collaborative projects such as the such as the N0TCH1 in CLL ROI (Ferrando & Dalla-Favera Co-PIs) and the Targeting P13K in T-ALL DOD grant (Ferrando & Diacovo (CRN) Co-PIs) reflecting a high level of intra-programmatic and inter-programmatic collaboration. In addition, members of the LDM participate in several multi-investigator projects with other NCI Centers, such as the Molecular Targets in B Cell Lymphoma and the Emerging targets in lymphoid malignancies Leukemia Lymphoma Society Specialized Center of Research (SCOR) grants.