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dc.contributor.authorMcArthur, K
dc.contributor.authorD'Cruz, AA
dc.contributor.authorSegal, D
dc.contributor.authorLackovic, K
dc.contributor.authorWilks, AF
dc.contributor.authorO'Donnell, JA
dc.contributor.authorNowell, CJ
dc.contributor.authorGerlic, M
dc.contributor.authorHuang, DCS
dc.contributor.authorBurns, CJ
dc.contributor.authorCroker, BA
dc.date.accessioned2020-12-21T02:27:08Z
dc.date.available2020-12-21T02:27:08Z
dc.date.issued2017-08-29
dc.identifierpii: 19678
dc.identifier.citationMcArthur, K., D'Cruz, A. A., Segal, D., Lackovic, K., Wilks, A. F., O'Donnell, J. A., Nowell, C. J., Gerlic, M., Huang, D. C. S., Burns, C. J. & Croker, B. A. (2017). Defining a therapeutic window for kinase inhibitors in leukemia to avoid neutropenia. ONCOTARGET, 8 (35), pp.57948-57963. https://doi.org/10.18632/oncotarget.19678.
dc.identifier.issn1949-2553
dc.identifier.urihttp://hdl.handle.net/11343/256932
dc.description.abstractNeutropenia represents one of the major dose-limiting toxicities of many current cancer therapies. To circumvent the off-target effects of cytotoxic chemotherapeutics, kinase inhibitors are increasingly being used as an adjunct therapy to target leukemia. In this study, we conducted a screen of leukemic cell lines in parallel with primary neutrophils to identify kinase inhibitors with the capacity to induce apoptosis of myeloid and lymphoid cell lines whilst sparing primary mouse and human neutrophils. We have utilized a high-throughput live cell imaging platform to demonstrate that cytotoxic drugs have limited effects on neutrophil viability but are toxic to hematopoietic progenitor cells, with the exception of the topoisomerase I inhibitor SN-38. The parallel screening of kinase inhibitors revealed that mouse and human neutrophil viability is dependent on cyclin-dependent kinase (CDK) activity but surprisingly only partially dependent on PI3 kinase and JAK/STAT signaling, revealing dominant pathways contributing to neutrophil viability. Mcl-1 haploinsufficiency sensitized neutrophils to CDK inhibition, demonstrating that Mcl-1 is a direct target for CDK inhibitors. This study reveals a therapeutic window for the kinase inhibitors BEZ235, BMS-3, AZD7762, and (R)-BI-2536 to induce apoptosis of leukemia cell lines whilst maintaining immunocompetence and hemostasis.
dc.languageEnglish
dc.publisherIMPACT JOURNALS LLC
dc.titleDefining a therapeutic window for kinase inhibitors in leukemia to avoid neutropenia
dc.typeJournal Article
dc.identifier.doi10.18632/oncotarget.19678
melbourne.affiliation.departmentMedical Biology (W.E.H.I.)
melbourne.affiliation.departmentSchool of Chemistry
melbourne.source.titleOncotarget
melbourne.source.volume8
melbourne.source.issue35
melbourne.source.pages57948-57963
dc.rights.licenseCC BY
melbourne.elementsid1234077
melbourne.contributor.authorBurns, Christopher
melbourne.contributor.authorSegal, David
melbourne.contributor.authorLackovic, Kurt
melbourne.contributor.authorHuang, David
melbourne.contributor.authorMcArthur, Kate
melbourne.contributor.authorO'Donnell, Joanne
dc.identifier.eissn1949-2553
melbourne.accessrightsOpen Access


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