Journal article
Acquired mutations in BAX confer resistance to BH3-mimetic therapy in acute myeloid leukemia
DM Moujalled, FC Brown, CC Chua, MA Dengler, G Pomilio, NS Anstee, V Litalien, E Thompson, T Morley, S MacRaild, IS Tiong, R Morris, K Dun, A Zordan, J Shah, S Banquet, E Halilovic, E Morris, MJ Herold, G Lessene Show all
Blood | AMER SOC HEMATOLOGY | Published : 2023
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..
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Awarded by Leukemia and Lymphoma Society
Funding Acknowledgements
This work was supported by fellowships and grants from the Australian National Health and Medical Research Council (Program grant 1016701) (D.C.S.H. and J.M.A.) , (1113577 and 1079560) (A.W.R.) , (1156024) (D.C.S.H.) , (Investigator grant 1176175) (F.C.B) , (1174902) (A.W.R.) , (1162809) (A.H.W.) , (Senior Research Fellowship 1156095) (M.J.H.) , Metcalf Family Fellowship (A.H.W.) ; Leukemia and Lymphoma Society, USA, Specialized Center of Research (grant 7015-18) (A.W.R., A.H.W., J.M.A., J.HA., and D.C.S.H.) ; Victorian Cancer Agency MCRF Fellowship (19011) (D.M.M.) and (grant 15018) (A.W.R. and A.H.W.) ; Cancer Council Victoria (grants-in-aid 1141740) (D.M.M.) ; Medical Research Future Fund (grant 1141460) (A.H.W.) ; Tour de Cure Foundation (RSP-212-2020) (D.M.M) ; Snowdome Foundation (P.B.) ; and the Australian Cancer Research Foundation.