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dc.contributor.authorSomers, K
dc.contributor.authorWen, VW
dc.contributor.authorMiddlemiss, SMC
dc.contributor.authorOsborne, B
dc.contributor.authorForgham, H
dc.contributor.authorJung, M
dc.contributor.authorKarsa, M
dc.contributor.authorClifton, M
dc.contributor.authorBongers, A
dc.contributor.authorGao, J
dc.contributor.authorMayoh, C
dc.contributor.authorRaoufi-Rad, N
dc.contributor.authorKusnadi, EP
dc.contributor.authorHannan, KM
dc.contributor.authorScott, DA
dc.contributor.authorKwek, A
dc.contributor.authorLiu, B
dc.contributor.authorFlemming, C
dc.contributor.authorChudakova, DA
dc.contributor.authorPandher, R
dc.contributor.authorFailes, TW
dc.contributor.authorLim, J
dc.contributor.authorAngeli, A
dc.contributor.authorOsterman, AL
dc.contributor.authorImamura, T
dc.contributor.authorKees, UR
dc.contributor.authorSupuran, CT
dc.contributor.authorPearson, RB
dc.contributor.authorHannan, RD
dc.contributor.authorDavis, TP
dc.contributor.authorMcCarroll, J
dc.contributor.authorKavallaris, M
dc.contributor.authorTurner, N
dc.contributor.authorGudkov, AV
dc.contributor.authorHaber, M
dc.contributor.authorNorris, MD
dc.contributor.authorHenderson, MJ
dc.date.accessioned2020-12-10T01:42:31Z
dc.date.available2020-12-10T01:42:31Z
dc.date.issued2019-05-16
dc.identifierpii: 10.1038/s41388-018-0666-5
dc.identifier.citationSomers, K., Wen, V. W., Middlemiss, S. M. C., Osborne, B., Forgham, H., Jung, M., Karsa, M., Clifton, M., Bongers, A., Gao, J., Mayoh, C., Raoufi-Rad, N., Kusnadi, E. P., Hannan, K. M., Scott, D. A., Kwek, A., Liu, B., Flemming, C., Chudakova, D. A. ,... Henderson, M. J. (2019). A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction. ONCOGENE, 38 (20), pp.3824-3842. https://doi.org/10.1038/s41388-018-0666-5.
dc.identifier.issn0950-9232
dc.identifier.urihttp://hdl.handle.net/11343/253770
dc.description.abstractSurvival 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.
dc.languageEnglish
dc.publisherNATURE PUBLISHING GROUP
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleA novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction
dc.typeJournal Article
dc.identifier.doi10.1038/s41388-018-0666-5
melbourne.affiliation.departmentSir Peter MacCallum Department of Oncology
melbourne.affiliation.departmentBiochemistry and Molecular Biology
melbourne.source.titleOncogene
melbourne.source.volume38
melbourne.source.issue20
melbourne.source.pages3824-3842
dc.rights.licenseCC BY
melbourne.elementsid1370291
melbourne.contributor.authorPearson, Richard
melbourne.contributor.authorHannan, Ross
melbourne.contributor.authorHannan, Katherine
melbourne.contributor.authorKusnadi, Eric
dc.identifier.eissn1476-5594
melbourne.accessrightsOpen Access


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