DNMT3A mutation coordinates epigenetic and translational regulation through orchestrating BCAA metabolism in acute myeloid leukemia

Acute myeloid leukemia (AML) harboring DNMT3A mutation exhibits epigenetic dysregulation, chemoresistance and poor outcome, but the underlining mechanism remains elusive. Here, inspired by the unexpected finding that DNMT3A-mutated AML patients exhibit a unique translatome landscape, we connected this epigenetic mutation to translational dysregulation through reprogrammed branched-chain amino acid (BCAA) metabolism. Particularly, DNMT3A mutation induces DNA hypomethylation-dependent activation of BCAT1, a rate-limiting aminotransferase gene for BCAA metabolism. Thereafter, the accumulation of intracellular BCAA more profoundly alters translation of a select subset of transcripts with higher BCAA codon ratios. Accordingly, deficiency in BCAA availability reduces the translation of target genes and attenuated the proliferative advantages of DNMT3A-mutated AML cells. More importantly, the pharmacological inhibition of BCAT1 with Gabapentin normalized BCAA levels, reversed target genes translation and repressed leukemia cell growth specifically in DNMT3A-mutated AML cells. Collectively, these findings uncovered a novel epigenetics-metabolism axis, in which DNMT3A mutation boosts BCAA metabolism thereby not only forming a positive feedback loop to enhance DNA hypomethylation through alpha ketoglutarate (α-KG)-dependent ten-eleven translocation (TET) activation, but also affecting gene translation in a BCAA codon-biased manner. Moreover, the efficacy of Gabapentin in suppressing AML cell proliferation highlights the clinical relevance of targeting BCAA metabolism to improve outcomes of DNMT3A-mutated AML.