Mutant NPM1-Regulated FTO-Mediated m6A Demethylation Promotes Leukemic Cell Survival via 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 N-6-methyladenosine (m(6)A) RNA modification has emerged as a new epigenetic modification to contribute to tumorigenesis and development. However, there is limited knowledge on the role of m(6)A modifications in NPM1-mutated AML. In this study, the decreased m(6)A level was first detected and high expression of fat mass and obesity-associated protein (FTO) was responsible for the m(6)A 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 m(6)A RNA demethylase activity to activate PDGFRB/ERK signaling axis. Our findings indicate that FTO-mediated m(6)A 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.

Automated summary

This study found decreased levels of m(6)A RNA modification in acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutations. The high expression of fat mass and obesity-associated protein (FTO) was responsible for the suppression of m(6)A modification. FTO upregulation facilitated leukemic cell survival through activating the PDGFRB/ERK signaling axis.