{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE296nnn/GSE296332/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Other"],"species":["Homo sapiens"],"gds_type":[" Expression profiling by high throughput sequencing","Other"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE296332"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"DNMT3A mutation coordinates epigenetic and translational regulation through orchestrating BCAA metabolism in acute myeloid leukemia","description":"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.","dates":{"publication":"2026/05/31"},"accession":"GSE296332","cross_references":{"GSM":["GSM8968709","GSM8968716","GSM8968713","GSM8968712","GSM8968715","GSM8968714","GSM8968711","GSM8968710"],"GPL":["20795"],"GSE":["296332"],"taxon":["Homo sapiens"]}}