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Using T cell acute lymphoblastic leukemia (T-ALL) as a model system, we identify FTO as a unique vulnerability in T cell leukemia. Knockout of\n            <jats:italic toggle=\"yes\">FTO<\/jats:italic>\n            , but not\n            <jats:italic toggle=\"yes\">ALKBH5<\/jats:italic>\n            , significantly suppresses leukemia initiation and progression. Mechanistic analysis reveals that FTO heightens\n            <jats:italic toggle=\"yes\">ELK3<\/jats:italic>\n            mRNA stability in an m\n            <jats:sup>6<\/jats:sup>\n            A-dependent manner. Elevated ELK3 in turn transcriptionally activates the expression of glycolytic genes. Pharmacological inhibition of FTO suppresses\n            <jats:italic toggle=\"yes\">ELK3<\/jats:italic>\n            expression, hampers glycolysis and manifests remarkable antileukemia efficacy. Our findings unravel the crucial role of FTO in T-ALL and highlight the FTO-ELK3 axis as a key nodule during leukemogenesis, thereby providing a fundamental basis to harness selective FTO antagonist for T-ALL therapeutics.\n          <\/jats:p>","DOI":"10.1126\/sciadv.adq3052","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T17:58:47Z","timestamp":1748455127000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":12,"title":["FTO regulates ELK3-mediated metabolic rewiring and represents a unique therapeutic target in T cell leukemia"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3144-809X","authenticated-orcid":true,"given":"Hao","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Hematology, Zhongnan Hospital of Wuhan University, State Key Laboratory of Metabolism and Regulation in Complex Organisms, Wuhan University, Wuhan, 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