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

Gauri Deb, Bettina Wingelhofer, Fabio Amaral, Alba Maiques-Diaz, John Chadwick, Gary Spencer, Emma Williams, Hui Sun Leong, Tamara Maes, Tim Somervaille

Research output: Contribution to journalArticlepeer-review


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 leukemic 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 up regulation 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.
Original languageEnglish
Pages (from-to)1266–1277
Publication statusPublished - 28 Nov 2019

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre


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