FTO regulates ELK3-mediated metabolic rewiring and represents a unique therapeutic target in T cell leukemia.

Understanding the regulation of N6-methyladenosine (m(6)A), the prominent internal modification in mRNA, fosters the development of potential therapeutic strategies for human cancers. While the m(6)A demethylases FTO and ALKBH5 are recognized for their crucial roles in various cancers, their impact on lymphoid leukemia remains uncertain. 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 FTO, but not ALKBH5, significantly suppresses leukemia initiation and progression. Mechanistic analysis reveals that FTO heightens ELK3 mRNA stability in an m(6)A-dependent manner. Elevated ELK3 in turn transcriptionally activates the expression of glycolytic genes. Pharmacological inhibition of FTO suppresses ELK3 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.