Mutant NPM1-Regulated FTO-Mediated m6A Demethylation Promotes Leukemic Cell Survival via PDGFRB/ERK Signaling Axis

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.

Cytoplasmic Expression of TP53INP2 Modulated by Demethylase FTO and Mutant NPM1 Promotes Autophagy in Leukemia Cells

“…Nevertheless, based on the fact that NPM1 mutants cannot directly regulate gene transcription [ 29 ], we deduced that other molecular events participate in the regulation of TP53INP2 transcripts. Considering our recent studies showed that NPM1-mA can stabilize m 6 A demethylase FTO to participate in the transcriptional regulation of target genes [ 30 ], we investigated whether FTO-mediated demethylation regulates the expression of TP53INP2 . Initially, several m 6 A methylated sites in the TP53INP2 mRNA were identified using the sequence-based RNA adenosine methylation site predictor (SRAMP) ( Figure 3 E).…”

“…Initially, we revealed that knockdown and overexpression of NPM1-mA affected the level of TP53INP2 transcripts. Considering NPM1-mA cannot directly regulate the transcription of target genes [ 29 ] but NPM1-mA can stabilize demethylase FTO to participate in transcriptional regulation [ 30 ], we investigated whether FTO-mediated demethylation modulates TP53INP2 expression. Then, the binding of TP53INP2 mRNA and FTO was confirmed by RIP experiments.…”

m6A mRNA methylation: Biological features, mechanisms, and therapeutic potentials in type 2 diabetes mellitus

“…A novel developed N6‐methyladenosine demethylase FTO small‐molecule inhibitor 18097 with a potent (IC 50 values 0.64 μmol/L) showed the suppressive effects on cell growth and lipogenesis in breast cancer cells 155 . Besides, recently, several small‐molecule compounds such as meclofenamate sodium, 156 FB23, 157 FB23‐2, 158 Dac51, 158 and bisantrene were reported to exhibit high efficacy of FTO inhibition 159 . However, whether these molecules improve the function, identity, and mass of β‐cell and IR in vivo and in vitro still warrants further investigation.…”

Novel insights into the interplay between m6A modification and programmed cell death in cancer

“…In GBM, the SPI1-induced downregulation of FTO promotes tumor progression by regulating pri-miR-10a processing in an m6A-dependent manner 66 . In contrast, for NPM1-mutated AML, which accounts for approximately one-third of AML cases, FTO is aberrantly overexpressed and serves as a carcinogen by promoting the cell cycle and inhibiting apoptosis 67 . Similarly, ALKBH5 promotes tumor growth and metastasis through the TRAF1-mediated activation of the NF-κB and MAPK signaling pathways in multiple myeloma 68 .…”