Acquired mutations in BAX confer resistance to BH3-mimetic therapy in acute myeloid leukemia
- Author(s)
- Moujalled, DM; Brown, FC; Chua, CC; Dengler, MA; Pomilio, G; Anstee, NS; Litalien, V; Thompson, E; Morley, T; MacRaild, S; Tiong, IS; Morris, R; Dun, K; Zordan, A; Shah, J; Banquet, S; Halilovic, E; Morris, E; Herold, MJ; Lessene, G; Adams, JM; Huang, DCS; Roberts, AW; Blombery, P; Wei, AH;
- Details
- Publication Year 2023,Volume 141,Issue #6,Page 634-644
- Journal Title
- Blood
- Publication Type
- Research article
- 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 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.
- Publisher
- American Society of Hematology
- Keywords
- Humans; Aged; bcl-2-Associated X Protein/genetics; Cell Line, Tumor; *Proto-Oncogene Proteins c-bcl-2/genetics; *Leukemia, Myeloid, Acute/drug therapy/genetics; Bridged Bicyclo Compounds, Heterocyclic/therapeutic use/pharmacology; Apoptosis; Mutation
- Department(s)
- Clinical Haematology; Pathology
- PubMed ID
- 36219880
- Publisher's Version
- https://doi.org/10.1182/blood.2022016090
- Open Access at Publisher's Site
https://doi.org/10.1182/blood.2022016090- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-06-13 07:55:03
Last Modified: 2023-06-13 07:56:08