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    Pre-clinical activity of combined LSD1 and mTORC1 inhibition in MLL-translocated acute myeloid leukaemia

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    Authors
    Deb, Gauri
    Wingelhofer, Bettina
    Amaral, Fabio
    Maiques-Diaz, Alba
    Chadwick, John A
    Spencer, Gary J
    Williams, Emma L
    Leong, Hui Sun
    Maes, T
    Somervaille, Tim CP
    Affiliation
    Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Oglesby Cancer Research Centre Building, 555 Wilmslow Road, Manchester, M20 4GJ, UK
    Issue Date
    2019
    
    Metadata
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    Abstract
    The histone demethylase lysine-specific demethylase 1 (LSD1 or KDM1A) has emerged as a candidate therapeutic target in acute myeloid leukaemia (AML); tranylcypromine-derivative inhibitors induce loss of clonogenic activity and promote differentiation, in particular in the MLL-translocated molecular subtype of AML. In AML, the use of drugs in combination often delivers superior clinical activity. To identify genes and cellular pathways that collaborate with LSD1 to maintain the leukaemic phenotype, and which could be targeted by combination therapies, we performed a genome-wide CRISPR-Cas9 dropout screen. We identified multiple components of the amino acid sensing arm of mTORC1 signalling-RRAGA, MLST8, WDR24 and LAMTOR2-as cellular sensitizers to LSD1 inhibition. Knockdown of mTORC1 components, or mTORC1 pharmacologic inhibition, in combination with LSD1 inhibition enhanced differentiation in both cell line and primary cell settings, in vitro and in vivo, and substantially reduced the frequency of clonogenic primary human AML cells in a modelled minimal residual disease setting. Synergistic upregulation of a set of transcription factor genes associated with terminal monocytic lineage differentiation was observed. Thus, dual mTORC1 and LSD1 inhibition represents a candidate combination approach for enhanced differentiation in MLL-translocated AML which could be evaluated in early phase clinical trials.
    Citation
    Deb G, Wingelhofer B, Amaral FMR, Maiques-Diaz A, Chadwick JA, Spencer GJ, et al. Pre-clinical activity of combined LSD1 and mTORC1 inhibition in MLL-translocated acute myeloid leukaemia. Leukemia. 2019:1-.
    Journal
    Leukemia
    URI
    http://hdl.handle.net/10541/622671
    DOI
    10.1038/s41375-019-0659-6
    PubMed ID
    31780813
    Additional Links
    https://dx.doi.org/10.1038/s41375-019-0659-6
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41375-019-0659-6
    Scopus Count
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    All Paterson Institute for Cancer Research

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