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


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 HIF1? expression. Silencing of HIF1? 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 HIF1?. 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 HIF1?/low MEIS1-expressing MLL-rearranged leukemia cells.

SUBMITTER: Somers K 

PROVIDER: S-EPMC6756102 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Somers Klaartje K   Wen Victoria W VW   Middlemiss Shiloh M C SMC   Osborne Brenna B   Forgham Helen H   Jung MoonSun M   Karsa Mawar M   Clifton Molly M   Bongers Angelika A   Gao Jixuan J   Mayoh Chelsea C   Raoufi-Rad Newsha N   Kusnadi Eric P EP   Hannan Kate M KM   Scott David A DA   Kwek Alan A   Liu Bing B   Flemming Claudia C   Chudakova Daria A DA   Pandher Ruby R   Failes Tim W TW   Lim James J   Angeli Andrea A   Osterman Andrei L AL   Imamura Toshihiko T   Kees Ursula R UR   Supuran Claudiu T CT   Pearson Richard B RB   Hannan Ross D RD   Davis Thomas P TP   McCarroll Joshua J   Kavallaris Maria M   Turner Nigel N   Gudkov Andrei V AV   Haber Michelle M   Norris Murray D MD   Henderson Michelle J MJ  

Oncogene 20190122 20


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 depola  ...[more]

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