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As most patients still develop recurrent disease, improved understanding of relapse mechanisms is needed. We find that 17% of patients relapsing after venetoclax-based therapy for AML have acquired inactivating missense or frameshift\/nonsense mutations in the apoptosis effector gene BAX. In contrast, such variants were rare after genotoxic chemotherapy. BAX variants arose within either leukemic or preleukemic compartments, with multiple mutations observed in some patients. In\u00a0vitro, AML cells with mutated BAX were competitively selected during prolonged exposure to BCL-2 antagonists. In model systems, AML cells rendered deficient for BAX, but not its close relative BAK, displayed resistance to BCL-2 targeting, whereas sensitivity to conventional chemotherapy was variable. Acquired mutations in BAX during venetoclax-based therapy represent a novel mechanism of resistance to BH3-mimetics and a potential barrier to the long-term efficacy of drugs targeting BCL-2 in AML.<\/jats:p>","DOI":"10.1182\/blood.2022016090","type":"journal-article","created":{"date-parts":[[2022,10,11]],"date-time":"2022-10-11T21:57:03Z","timestamp":1665525423000},"page":"634-644","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":109,"title":["Acquired mutations in BAX confer resistance to BH3-mimetic therapy in acute myeloid leukemia"],"prefix":"10.1182","volume":"141","author":[{"given":"Donia M.","family":"Moujalled","sequence":"first","affiliation":[{"name":"1Australian Centre for Blood Diseases, Monash University, Melbourne, Australia"},{"name":"2Department of Clinical Haematology, The Alfred, Melbourne, Australia"},{"name":"3Walter and Eliza Hall Institute of Medical Research, Melbourne, 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