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Epigenetics

A non-coding m6A reader promotes leukaemia

Nature Cell Biology volume 25, pages 1247–1249 (2023)Cite this article

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Pathways linked to the modification of RNA with N6-methyladenosine (m6A) are known to be involved in initiating and maintaining cancer. But many of the key components of these pathways remain undiscovered. The RBFOX2 protein has now been identified as an m6A reader involved in locus-specific chromatin regulation, with therapeutic implications for myeloid leukaemia.

The modification of eukaryotic mRNAs and non-coding RNAs with N6-methyladenosine (m6A) is implicated in a range of physiological and disease processes, including cancer1. Regulated by methyltransferase ‘writers’ (such as METTL3 and METTL16), demethylase ‘erasers’ (including FTO and ALKBH5), and a growing list of ‘readers’ (such as YTHDC1/2, YTHDF1/2/3 and IGF2BP1/2/3), m6A has substantial impacts on RNA metabolism. In acute myeloid leukaemia (AML), these components are frequently overexpressed, and are essential to the survival of leukaemia stem cells (LSCs)2,3,4,5,6,7. Notably, the m6A writer METTL3 — which enhances the translation of cancer-associated transcripts — is susceptible to pharmacological inhibition in preclinical studies, and a first-in-class treatment is advancing through clinical trials8,9,10. The m6A reader YTHDC1 is also important in AML, as it protects key m6A-modified mRNAs within nuclear condensates2. In addition, YTHDC1 facilitates the decay of a subset of m6A-modified RNAs that contribute to chromatin silencing11.

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Fig. 1: Binding of RBFOX2 to m6A-modified caRNAs regulates gene expression in myeloid leukaemia.

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Authors and Affiliations

  1. Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK

    James Russell & Konstantinos Tzelepis

  2. Department of Haematology, University of Cambridge, Cambridge, UK

    James Russell & Konstantinos Tzelepis

  3. Milner Therapeutics Institute, University of Cambridge, Cambridge, UK

    Konstantinos Tzelepis

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  1. James Russell
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  2. Konstantinos Tzelepis
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Correspondence to Konstantinos Tzelepis.

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Russell, J., Tzelepis, K. A non-coding m6A reader promotes leukaemia. Nat Cell Biol 25, 1247–1249 (2023). https://doi.org/10.1038/s41556-023-01205-w

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