Targeting bcaa metabolism induces synthetic lethality in DNMT3A-mutated acute myeloid leukemia

Abstract DNA methyltransferase 3A (DNMT3A)-mutant acute myeloid leukemia (AML) exhibits epigenetic dysregulation and chemoresistance, but the molecular pathways connecting DNA hypomethylation to leukemogenesis remain elusive. This study linked DNMT3A mutations to translational regulation via branched-chain amino acid (BCAA) metabolic reprogramming. Mechanistically, DNMT3A mutation induced promoter hypomethylation and transcriptional upregulation of BCAT1, whose protein is a rate-limiting enzyme in BCAA metabolism, thus resulting in intracellular BCAA accumulation. Crucially, pharmacological BCAT1 inhibition (Gabapentin) restored BCAA homeostasis and elicited synthetic lethality specifically in mutant cells. BCAA accumulation drove codon-biased translational regulation that elevated BCAA levels acted as translational substrates to enhance tRNA charging, thereby accelerating translation elongation and selectively amplifying the synthesis of proteins critical for ATP metabolism and lipid homeostasis. This codon-biased translational regulation sustained the myeloid differentiation bias in mice, a hallmark of DNMT3A-mutated AML pathogenesis. BCAA restriction similarly attenuated target gene translation, restored myeloid differentiation and enhanced synthetic lethality in preclinical models. Our results also delineated a previously unrecognized epigenetic-metabolic circuit: DNMT3A mutations hyperactivated BCAA metabolism, establishing a self-reinforcing loop through a-ketoglutarate (a-KG)-mediated TET enzyme activation (amplifying DNA hypomethylation) while imposing codon-biased translational regulation. These findings not only established BCAT1 as a key effector of DNMT3A mutation-driven leukemogenesis but also revealed tRNA charging as a previously unrecognized mechanism coupling amino acid metabolism to oncogenic translation. The efficacy of Gabapentin and deficient BCAA supply in suppressing AML progression highlighted the clinical relevance of targeting BCAA metabolism to overcome differentiation arrest and improve outcomes in this high-risk AML subset.