Mixed Lineage Leukaemia (MLL) gene rearrangement defines a large subset of infant leukaemia with poor prognosis. Current therapeutic strategies for these patients are limited and novel therapies are urgently needed to improve disease outcome. The aim of this study was to identify a novel small molecule inhibitor that selectively targets MLL cells.

High-throughput screening of 34,000 diverse small molecules identified SM6 as a selective inhibitor of an infant MLL-rearranged leukaemia cell line, PER485. Cytotoxicity testing of SM6 across 24 cell lines demonstrated that the compound decreased viability of leukaemia cells harbouring the MLL-AF4 or MLL-AF9 rearrangements, as well as the CALM-AF10 fusion, while other leukaemias, solid tumours and normal peripheral blood cells were less sensitive. SM6 induced caspase-mediated apoptosis in MLL-rearranged leukaemia cell lines as demonstrated by rapid mitochondrial depolarization, increased AnnexinV staining, caspase activation and PARP cleavage within a few hours of treatment. Polysomal profiling revealed a robust SM6-induced reduction in polysomes suggesting decreased protein translation rates following treatment. The drop in protein translation occurred even when cell death was inhibited by the pan-caspase inhibitor Q-VD-Oph demonstrating that the observed repression in protein translation was not due to apoptotic processes. Through its effect on protein translation, SM6 induced reversal of the hallmark pattern of MLL-rearranged gene expression exemplified by decreased protein levels of leukaemogenic HoxA9 and Meis1.

Thus, we identified a protein translation inhibitor that rapidly and selectively induced apoptosis in MLL-rearranged leukaemia. This study showed for the first time that the protein synthesis machinery constitutes a novel therapeutic target in MLL-rearranged leukaemia