Acquired mutations in BAX confer resistance to BH3-mimetic therapy in Acute Myeloid Leukemia.
Donia M MoujalledFiona C BrownChong Chyn ChuaMichael A DenglerGiovanna PomilioNatasha S AnsteeVeronique LitalienElla R ThompsonThomas David MorleySarah MacRaildIng Soo TiongRhiannon MorrisKaren DunAdrian Carl ZordanJaynish S ShahSébastien BanquetEnsar HalilovicErick J MorrisMarco J HeroldGuillaume L LesseneJerry M AdamsDavid Ching Siang HuangAndrew W RobertsPiers BlomberyAndrew H WeiPublished in: Blood (2022)
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 pre-leukemic 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 represents a novel mechanism of resistance to BH3-mimetics and a potential barrier to longer-term efficacy of drugs targeting BCL-2 in AML.
Keyphrases
- acute myeloid leukemia
- induced apoptosis
- end stage renal disease
- ejection fraction
- endoplasmic reticulum stress
- chronic kidney disease
- newly diagnosed
- clinical trial
- oxidative stress
- cell cycle arrest
- multiple sclerosis
- signaling pathway
- prognostic factors
- copy number
- stem cells
- magnetic resonance
- rheumatoid arthritis
- gene expression
- immune response
- dna methylation
- bone marrow
- autism spectrum disorder
- risk assessment
- preterm infants
- regulatory t cells
- cancer therapy
- study protocol
- preterm birth
- pi k akt
- chronic lymphocytic leukemia
- phase ii
- rectal cancer
- disease activity