Dynamic BH3 profiling method for rapid identification of active therapy in BH3 mimetics resistant xenograft mouse models

The clinical effectiveness of BH3 mimetics therapy is limited by the inevitable emergence of acquired resistance. We present a protocol to model in vivo acquired resistance to BH3 mimetics in patient-derived xenograft (PDX) mouse models of acute myeloid leukemia. Using resistant PDXs as a valuable model, we next introduce a protocol for dynamic BH3 profiling (DBP) method. DBP allows functional identification of effective drug therapies based on measurements of drug-induced apoptosis signaling to overcome in vivo BH3 mimetics resistance. For complete details on the use and execution of this protocol, please refer to Bhatt et al. (2020). [Display omitted] •Generating in vivo PDX mouse models with acquired resistance to BH3 mimetics•Isolating human myeloblasts from the bone marrow and spleen of leukemia-engrafted mice•Identifying drug sensitivities of resistant myeloblasts using dynamic BH3 profiling The clinical effectiveness of BH3 mimetics therapy is limited by the inevitable emergence of acquired resistance. We present a protocol to model in vivo acquired resistance to BH3 mimetics in patient-derived xenograft (PDX) mouse models of acute myeloid leukemia. Using resistant PDXs as a valuable model, we next introduce a protocol for dynamic BH3 profiling (DBP) method. DBP allows functional identification of effective drug therapies based on measurements of drug-induced apoptosis signaling to overcome in vivo BH3 mimetics resistance.