1. A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction.
- Author
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Somers K, Wen VW, Middlemiss SMC, Osborne B, Forgham H, Jung M, Karsa M, Clifton M, Bongers A, Gao J, Mayoh C, Raoufi-Rad N, Kusnadi EP, Hannan KM, Scott DA, Kwek A, Liu B, Flemming C, Chudakova DA, Pandher R, Failes TW, Lim J, Angeli A, Osterman AL, Imamura T, Kees UR, Supuran CT, Pearson RB, Hannan RD, Davis TP, McCarroll J, Kavallaris M, Turner N, Gudkov AV, Haber M, Norris MD, and Henderson MJ
- Subjects
- Animals, Cell Line, Tumor, Drug Resistance, Neoplasm drug effects, Gene Expression Regulation, Leukemic drug effects, Gene Rearrangement, Histone-Lysine N-Methyltransferase genetics, Humans, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Mice, Inbred Strains, Mitochondria physiology, Myeloid Ecotropic Viral Integration Site 1 Protein genetics, Myeloid-Lymphoid Leukemia Protein genetics, Unfolded Protein Response drug effects, Acrylates pharmacology, Antineoplastic Agents pharmacology, Furans pharmacology, Leukemia, Myeloid, Acute drug therapy, Mitochondria drug effects, Nitriles pharmacology
- Abstract
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.
- Published
- 2019
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