Abstract
AbstractAcute myeloid leukemia (AML) is the most common hematopoietic malignancies, and chemotherapy resistance is one of the main causes of relapse. Because of lower survival rate for patients with relapse, it is pivotal to identify etiological factors responsible for chemo-resistance. In this work, direct MeRIP-seq analysis of sequential samples at stage of complete remission (CR) and relapse identifies that dysregulated N6-methyladenosine (m6A) methylation is involved in this progression, and hypomethylated RNAs are related to cell differentiation. m6A demethylase FTO is overexpressed in relapse samples, which enhances the drug resistance of AML cells in vivo and in vitro. In addition, FTO knockdown cells exhibit stronger capacity of differentiation towards granules and myeloid lineages after cytosine arabinoside (Ara-C) treatment. Mechanistically, FOXO3 is identified as a downstream target of FTO, the hypomethylation of FOXO3 mRNA affects its RNA degradation and further reduces its own expression, which ultimately result in attenuated cell differentiation. Collectively, these results demonstrate that FTO-m6A-FOXO3 is the main regulatory axis to affect the chemotherapy resistance of AML cells and FTO is a potential therapeutic target of chemotherapy resistance in AML.
Funder
National Natural Science Foundation of China
China Postdoctoral Science Foundation
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Cell Biology,Cellular and Molecular Neuroscience,Immunology
Cited by
3 articles.
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