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    Targeting the RNA m(6)A reader YTHDF2 selectively compromises cancer stem cells in acute myeloid leukemia

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    Authors
    Paris, J
    Morgan, M
    Campos, J
    Spencer, Gary J
    Shmakova, A
    Ivanova, I
    Mapperley, C
    Lawson, H
    Wotherspoon, DA
    Sepulveda, C
    Vukovic, M
    Allen, L
    Sarapuu, A
    Tavosanis, A
    Guitart, AV
    Villacreces, A
    Much, C
    Choe, J
    Azar, A
    van de Lagemaat, LN
    Vernimmen, D
    Nehme, A
    Mazurier, F
    Somervaille, Tim CP
    Gregory, RI
    O'Carroll, D
    Kranc, KR
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    Affiliation
    MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK;
    Issue Date
    2019
    
    Metadata
    Show full item record
    Abstract
    Acute myeloid leukemia (AML) is an aggressive clonal disorder of hematopoietic stem cells (HSCs) and primitive progenitors that blocks their myeloid differentiation, generating self-renewing leukemic stem cells (LSCs). Here, we show that the mRNA m6A reader YTHDF2 is overexpressed in a broad spectrum of human AML and is required for disease initiation as well as propagation in mouse and human AML. YTHDF2 decreases the half-life of diverse m6A transcripts that contribute to the overall integrity of LSC function, including the tumor necrosis factor receptor Tnfrsf2, whose upregulation in Ythdf2-deficient LSCs primes cells for apoptosis. Intriguingly, YTHDF2 is not essential for normal HSC function, with YTHDF2 deficiency actually enhancing HSC activity. Thus, we identify YTHDF2 as a unique therapeutic target whose inhibition selectively targets LSCs while promoting HSC expansion.
    Citation
    Paris J, Morgan M, Campos J, Spencer GJ, Shmakova A, Ivanova I, et al. Targeting the RNA m(6)A reader YTHDF2 selectively compromises cancer stem cells in acute myeloid leukemia. Cell Stem Cell. 2019 Apr 24.
    Journal
    Cell Stem Cell
    URI
    http://hdl.handle.net/10541/621869
    DOI
    10.1016/j.stem.2019.03.021
    PubMed ID
    31031138
    Additional Links
    https://dx.doi.org/10.1016/j.stem.2019.03.021
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.stem.2019.03.021
    Scopus Count
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    All Paterson Institute for Cancer Research

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