Somers, KlaartjeWen, V. W.Middlemiss, S. M. C.Osborne, B.Forgham, H.Jung, MoonSunKarsa, MawarClifton, MollyBongers, AngelikaGao, JixuanHannan, KatherineHannan, Ross2019-12-172019-12-170950-9232http://hdl.handle.net/1885/195675Survival rates for pediatric patients suffering from mixed lineage leukemia (MLL)-rearranged leukemia remain below 50% and more targeted, less toxic therapies are urgently needed. A screening method optimized to discover cytotoxic compounds selective for MLL-rearranged leukemia identified CCI-006 as a novel inhibitor of MLL-rearranged and CALM-AF10 translocated leukemias that share common leukemogenic pathways. CCI-006 inhibited mitochondrial respiration and induced mitochondrial membrane depolarization and apoptosis in a subset (7/11, 64%) of MLL-rearranged leukemia cell lines within a few hours of treatment. The unresponsive MLL-rearranged leukemia cells did not undergo mitochondrial membrane depolarization or apoptosis despite a similar attenuation of mitochondrial respiration by the compound. In comparison to the sensitive cells, the unresponsive MLL-rearranged leukemia cells were characterized by a more glycolytic metabolic phenotype, exemplified by a more pronounced sensitivity to glycolysis inhibitors and elevated HIF1α expression. Silencing of HIF1α expression sensitized an intrinsically unresponsive MLL-rearranged leukemia cell to CCI-006, indicating that this pathway plays a role in determining sensitivity to the compound. In addition, unresponsive MLL-rearranged leukemia cells expressed increased levels of MEIS1, an important leukemogenic MLL target gene that plays a role in regulating metabolic phenotype through HIF1α. MEIS1 expression was also variable in a pediatric MLL-rearranged ALL patient dataset, highlighting the existence of a previously undescribed metabolic variability in MLL-rearranged leukemia that may contribute to the heterogeneity of the disease. This study thus identified a novel small molecule that rapidly kills MLL-rearranged leukemia cells by targeting a metabolic vulnerability in a subset of low HIF1α/low MEIS1-expressing MLL-rearranged leukemia cells.This research was supported by NHMRC, Leukemia Foundation, Anthony Rothe Memorial Trust, NSW Cancer Council, Cancer Institute NSW, Tenix Foundation, ISG Foundation and the Children’s Leukemia & Cancer Research Foundation, Perth.application/pdfen-AU© 2019 The Author(s)http://creativecommons.org/licenses/by/4.0/2019-01-2210.1038/s41388-018-0666-52019-07-28Creative Commons Attribution 4.0 International License