Pre-clinical activity of combined LSD1 and mTORC1 inhibition in MLL-translocated acute myeloid leukaemia
Authors
Deb, GauriWingelhofer, 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, UKIssue Date
2019
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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
LeukemiaDOI
10.1038/s41375-019-0659-6PubMed ID
31780813Additional Links
https://dx.doi.org/10.1038/s41375-019-0659-6Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1038/s41375-019-0659-6
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