title: Sustained inhibition of STAT5, but not JAK2, is essential for TKI-induced cell death in chronic myeloid leukemia.
abstract: Kinase inhibitors block proliferative signals in BCR-ABL1+ leukemic cells, but their capacity to induce apoptosis is poorly understood. Initial studies suggested that very brief exposure to kinase inhibitors was sufficient to induce apoptosis in chronic myeloid leukemia (CML) cells. However, flaws in this experimental model have subsequently been identified, leading to the conclusion that apoptosis only occurs with sustained low-level kinase inhibition. Thus, the minimum duration of complete kinase inhibition required to commit CML cells to death is unknown. Here we confirm that <1 h is insufficient to induce significant commitment to death in BCR-ABL1+ cell lines and in primary CD34+ progenitor cells, and establish that commitment to cell death only occurs if kinase inhibition is maintained for 4 h or more. Remarkably, signal transducer and activator of transcription 5 (STAT5) inhibition in combination with transient (<1 h) tyrosine kinase inhibitor (TKI) exposure proved lethal for CML progenitors, despite the reactivation of Bcr-Abl after 1 h. JAK kinase inhibition did not induce cell death in combination with transient TKI exposure. Thus, STAT5 appears to be a critical determinant of the time-dependent sensitivity of CML progenitor cells to TKI treatment in a Bcr-Abl-dependent, but JAK-independent, manner. We conclude that combining kinase inhibition with STAT5 inhibition represents a promising therapeutic approach in BCR-ABL1+ leukemias.
authors.affiliation: 1] Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia [2] Centre for Personalised Cancer Medicine (CPCM), Faculty of Health Science, University of Adelaide, Adelaide, South Australia, Australia [3] School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: L
authors.initials: L
authors.lastname: Schafranek
authors.affiliation: 1] Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia [2] Centre for Personalised Cancer Medicine (CPCM), Faculty of Health Science, University of Adelaide, Adelaide, South Australia, Australia [3] School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: E
authors.initials: E
authors.lastname: Nievergall
authors.affiliation: 1] Discipline of Paediatrics, Faculty of Health Science, University of Adelaide, Adelaide, South Australia, Australia [2] Department of Immunology, SA Pathology, Adelaide, South Australia, Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Powell
authors.affiliation: 1] School of Medicine, University of Adelaide, Adelaide, South Australia, Australia [2] Department of Haematology, SA Pathology, Adelaide, South Australia, Australia.
authors.forename: D K
authors.initials: DK
authors.lastname: Hiwase
authors.affiliation: 1] Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia [2] School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Leclercq
authors.affiliation: 1] Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia [2] Centre for Personalised Cancer Medicine (CPCM), Faculty of Health Science, University of Adelaide, Adelaide, South Australia, Australia [3] School of Medicine, University of Adelaide, Adelaide, South Australia, Australia [4] Department of Haematology, SA Pathology, Adelaide, South Australia, Australia [5] Centre for Cancer Biology, University of South Australia, Adelaide, South Australia, Australia.
authors.forename: T P
authors.initials: TP
authors.lastname: Hughes
authors.affiliation: 1] Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia [2] Centre for Personalised Cancer Medicine (CPCM), Faculty of Health Science, University of Adelaide, Adelaide, South Australia, Australia [3] School of Medicine, University of Adelaide, Adelaide, South Australia, Australia [4] Discipline of Paediatrics, Faculty of Health Science, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: D L
authors.initials: DL
authors.lastname: White
mesh_terms: D018952:Antigens, CD34 / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D016313:Genes, abl; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors*
chemical_list: D018952:Antigens, CD34; D047428:Protein Kinase Inhibitors; D050799:STAT5 Transcription Factor; D053614:Janus Kinase 2