Acquired mutations in BAX confer resistance to BH3-mimetic therapy in acute myeloid leukemia.

ABSTRACT: Randomized trials in acute myeloid leukemia (AML) have demonstrated improved survival by the BCL-2 inhibitor venetoclax combined with azacitidine in older patients, and clinical trials are actively exploring the role of venetoclax in combination with intensive chemotherapy in fitter patients with AML. 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 vitro, AML cells

SUBMITTER: Moujalled DM 

PROVIDER: S-EPMC10651776 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature