Abstract
Neutropenia 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.
Highlights
Acute Myeloid Leukaemia (AML) is a heterogeneous disease characterised by an abundance of mutations in genes encoding signalling proteins, transcription factors, tumor suppressors and chromatin modifying proteins [1]
We have used a live-cell imaging platform previously developed by us to determine if these compounds induce apoptosis of neutrophils and hematopoietic progenitor cells, as a method of assessing their potential to cause neutropenia. With this combined experimental design we have identified individual kinase inhibitors that provide a therapeutic window for the effective treatment of leukemias with minimal effects on neutrophil viability
The activity of the kinase inhibitor collection against a panel of human leukemia cell lines was determined in cell viability assays run over 48 h using the Cell Titer Glo reagent
Summary
Acute Myeloid Leukaemia (AML) is a heterogeneous disease characterised by an abundance of mutations in genes encoding signalling proteins, transcription factors, tumor suppressors and chromatin modifying proteins [1]. Less than 40% of adults with AML are cured, with the situation being poor for the elderly who often have co-morbid conditions, where median survival is www.impactjournals.com/oncotarget approximately 10 months [3]. Against this backdrop there has been a concerted effort over the last decade to develop targeted therapies for AML, with the aim to target specific genetic lesions driving oncogenesis [4]. T-ALL displays a variety of genetic complexities arising from mutations in signalling proteins, transcription factors and tumor suppressors. BCR-ABL inhibitors such as imatinib, nilotinib and dasatinib may be of use to ALL patients with ABL fusion proteins [8]
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