Mutant NPM1-Regulated FTO-Mediated mA Demethylation Promotes Leukemic Cell Survival PDGFRB/ERK Signaling Axis.

Acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutations exhibits distinct biological and clinical features, accounting for approximately one-third of AML. Recently, the -methyladenosine (mA) RNA modification has emerged as a new epigenetic modification to contribute to tumorigenesis and development. However, there is limited knowledge on the role of mA modifications in NPM1-mutated AML. In this study, the decreased mA level was first detected and high expression of fat mass and obesity-associated protein (FTO) was responsible for the mA suppression in NPM1-mutated AML. FTO upregulation was partially induced by NPM1 mutation type A (NPM1-mA) through impeding the proteasome pathway. Importantly, FTO promoted leukemic cell survival by facilitating cell cycle and inhibiting cell apoptosis. Mechanistic investigations demonstrated that FTO depended on its mA RNA demethylase activity to activate PDGFRB/ERK signaling axis. Our findings indicate that FTO-mediated mA demethylation plays an oncogenic role in NPM1-mutated AML and provide a new layer of epigenetic insight for future treatments of this distinctly leukemic entity.