A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction.

Oncogene (2019-01-24)
Klaartje Somers, Victoria W Wen, Shiloh M C Middlemiss, Brenna Osborne, Helen Forgham, MoonSun Jung, Mawar Karsa, Molly Clifton, Angelika Bongers, Jixuan Gao, Chelsea Mayoh, Newsha Raoufi-Rad, Eric P Kusnadi, Kate M Hannan, David A Scott, Alan Kwek, Bing Liu, Claudia Flemming, Daria A Chudakova, Ruby Pandher, Tim W Failes, James Lim, Andrea Angeli, Andrei L Osterman, Toshihiko Imamura, Ursula R Kees, Claudiu T Supuran, Richard B Pearson, Ross D Hannan, Thomas P Davis, Joshua McCarroll, Maria Kavallaris, Nigel Turner, Andrei V Gudkov, Michelle Haber, Murray D Norris, Michelle J Henderson
RESUMEN

Survival 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.

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MISSION® esiRNA, targeting human HIF1A