Abstract

Acute myeloid leukemia (AML) with nucleophosmin 1 (NPM1) mutations exhibits distinct biological and clinical features, accounting for approximately one-third of AML. Recently, the N6-methyladenosine (m6A) RNA modification has emerged as a new epigenetic modification to contribute to tumorigenesis and development. However, there is limited knowledge on the role of m6A modifications in NPM1-mutated AML. In this study, the decreased m6A level was first detected and high expression of fat mass and obesity-associated protein (FTO) was responsible for the m6A 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 m6A RNA demethylase activity to activate PDGFRB/ERK signaling axis. Our findings indicate that FTO-mediated m6A 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.

Highlights

  • Acute myeloid leukemia (AML), a heterogeneous hematologic malignancy, is the most common form of acute leukemia among adults [1]

  • To explore whether the abnormal m6A level exists in acute myeloid leukemia (AML) with Nucleophosmin 1 (NPM1) mutations, we first detected the m6A level of global RNAs

  • The results showed that fat mass and obesity-associated protein (FTO) messenger RNAs (mRNAs) level was significantly elevated in NPM1-mutated AML cases in comparison with NPM1-unmutated AML cases (Figures 1B, C)

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Summary

Introduction

Acute myeloid leukemia (AML), a heterogeneous hematologic malignancy, is the most common form of acute leukemia among adults [1]. Deeper explorations of underlying molecular mechanisms contributing to NPM1-mutated AML and novel therapeutic targets are imperative

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