A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction
Klaartje Somers, Victoria W Wen, Shiloh MC 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 Show all
ONCOGENE | NATURE PUBLISHING GROUP | Published : 2019
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 membr..View full abstract
Awarded by NCI Cancer Center Support Grant
Awarded by NATIONAL CANCER INSTITUTE
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. Metabolic analysis was performed at the Cancer Metabolism Core, SBP Medical Discovery Institute, with assistance from Olga Zagnitko and support of NCI Cancer Center Support Grant P30 CA30199.