Chronic Lymphocytic Leukemia (CLL) is the most prevalent hematologic malignancy among the aging population in the Western world and remains largely incurable. Besides chronic B-cell receptor activation to ensure their survival, CLL cells interact with and shape a microenvironment favourable to their survival and proliferation. CLL cells migrate to favourable niches (lymph nodes and bone marrow), where they interact with resident stromal cells and actively recruit T lymphocytes through soluble factors, and in turn T-cells ensure CLL cell survival. The protective microenvironment enhances CLL cell resistance to conventional therapeutics. The aim of my project is to decipher the processes regulating CLL cell migration to and retention in protective niches. We will attempt to delineate the underlying molecular mechanisms regulating these processes, and in particular the involvement of the PI3K pathway in the context of ZAP-70 overexpression. A better understanding of the processes governing CLL cell interaction with its microenvironment will aid in the design of targeted therapeutics that disrupt it, enhancing CLL cell vulnerability.