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The signaling cascade that triggers the B cell mediated immune-response upon antigen binding to the B cell receptor is critically dependent on Bruton’s tyrosine kinase (BTK). The BCR signaling pathway remains critical for survival and proliferation of transformed B cells. The introduction of BTK inhibitors (BTKi) to interfere with this signaling pathway has revolutionized treatment of chronic lymphocytic leukemia (CLL). In CLL, BTKi treatment cause tumor cells to exit tissues and enter peripheral blood where they over time waste away.Long-term BTKi treatment is burdened by side effects and the development of treatment resistant CLL. Curiously, the cessation of BTKi treatment is not associated with disease progression. Instead, many patients remain in long-term sustained remission. This suggests that BTKi can induce changes to CLL cells or tumor microenvironment (TME) that persist long-term.The proposed project aims to:1. Perform temporal analysis of plasma biomarkers and CLL cells during treatment with 2nd generation BTKi.2. Disentangle direct and TME mediated effects of BTKi treatment on CLL using a combined BTKi resistance (BTK C481S) and CLL mouse model.3. Identify CLL-intrinsic and TME mediated factors contributing to long-term sustained remission after the withdrawal of BTKi treatment.Our hope is that this will lead to improved understanding of how BTK inhibitors work and how they can be used to provide each individual patient with the best possible treatment.