M6A demethylase FTO in leukemia: Function, molecular mechanisms, and therapeutic implications.

Fat mass and obesity-associated protein (FTO) is a Fe(II)/2-oxoglutarate-dependent RNA demethylase that removes the N6-methyladenosine (m6A) mark and rewires post-transcriptional gene control. In leukemia, FTO is often overexpressed and promotes leukemogenesis by increasing the stability and translation of mRNAs that govern differentiation, metabolism, and survival. In acute myeloid leukemia (AML), FTO-dependent m6A erasure is associated with impaired differentiation (e.g., ASB2/RARA), reinforcement of MYC/CEBPA programs, and glycolytic and stress-adaptation pathways that support therapy resistance and relapse. In acute lymphoblastic leukemia (ALL), FTO contributes to disease maintenance through metabolic rewiring (e.g., ELK3-driven glycolysis), repression of tumor-suppressive transcripts (e.g., IRF8), and stabilization of ribosome-biogenesis mRNAs that sustain proliferative fitness, with additional influence from microenvironmental cues such as exosome-mediated transfer. Preclinical studies show that genetic depletion, small-molecule inhibition, or targeted degradation of FTO increases m6A on key targets, suppresses leukemic growth, and can sensitize cells to standard therapies, supporting FTO as a druggable epitranscriptomic vulnerability. This review summarizes FTO structure and function, highlights subtype-specific mechanisms in AML and ALL, and discusses emerging therapeutic strategies and translational challenges.