SUMMARY N6-methyladenosine (m6A) represents the most prevalent internal modification in mammalian mRNAs. Despite its functional importance in various fundamental bioprocesses, the studies of m6A in cancer have been limited. Here we show that FTO, as an m6A demethylase, plays a critical oncogenic role in acute myeloid leukemia (AML). FTO is highly expressed in AMLs with t(11q23)/MLL-rearrangements, t(15;17)/PML-RARA, FLT3-ITD and/or NPM1 mutations. FTO enhances leukemic oncogene-mediated cell transformation and leukemogenesis, and inhibits all-trans-retinoic acid (ATRA)-induced AML cell differentiation, through regulating expression of targets such as ASB2 and RARA by reducing m6A levels in these mRNA transcripts. Collectively, our study demonstrates the functional importance of the m6A methylation and the corresponding proteins in cancer, and provides profound insights into leukemogensis and drug response.

N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic messenger RNAs (mRNAs), has been shown to play critical roles in various normal bioprocesses such as tissue development, stem cell self-renewal and differentiation, heat shock or DNA damage response, and maternal-to-zygotic transition. The m6A modification is deposited by the m6A methyltransferase complex (MTC; i.e., writer) composed of METTL3, METTL14 and WTAP, and probably also VIRMA and RBM15, and can be removed by m6A demethylases (i.e., erasers) such as FTO and ALKBH5. The fates of m6A-modified mRNAs rely on the functions of distinct proteins that recognize them (i.e., readers), which may affect the stability, splicing, and/or translation of target mRNAs. Given the functional importance of the m6A modification machinery in normal bioprocesses, it is not surprising that evidence is emerging that dysregulation of m6A modification and the associated proteins also contributes to the initiation, progression, and drug response of cancers. In this review, we focus on recent advances in the study of biological functions and the underlying molecular mechanisms of dysregulated m6A modification and the associated machinery in the pathogenesis and drug response of various types of cancers. In addition, we also discuss possible therapeutic interventions against the dysregulated m6A machinery to treat cancers.

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Highlights d Development of two potent FTO inhibitors with IC 50 values in the low nanomolar range d KD of FTO or pharmacological inhibition of FTO suppresses LSC/LIC self-renewal d Targeting FTO suppresses immune checkpoint gene expression and immune evasion d Targeting FTO by potent inhibitors holds therapeutic promise against various cancers