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

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.