Andrew Wei, MBBS, PhD, Alfred Hospital and Monash University, Melbourne, Australia, discusses a study aiming to observe the mechanisms behind resistance to BH3 mimetics, such as the BCL-2 inhibitor, venetoclax, in acute myeloid leukemia (AML) patients. Preclinical trials using various technologies, for example, CRISPR screens, have established that deficiencies or mutations in BAX, a downstream BCL-2 protein, lead to venetoclax resistance. In this study, 14% of the patients who relapsed after venetoclax treatment were found to have BAX mutations. In contrast, patients who relapsed after traditional chemotherapy had no such mutations. This suggests that the mechanism of BAX-mediated resistance is specific to BH3 mimetic treatment. Models of BAX deficiency were developed using CRISPR and resistance to BH3 mimetics was induced to find that BAX deficiency and mutations confer resistance not only to venetoclax but also an MCL1 inhibitor. No chemoresistance was observed in the models produced. This interview took place during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, 2020.