title: JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of CML CD34+ cells in vitro and in vivo.
abstract: Chronic myeloid leukemia (CML) stem cell survival is not dependent on BCR-ABL protein kinase and treatment with ABL tyrosine kinase inhibitors cures only a minority of CML patients, thus highlighting the need for novel therapeutic targets. The Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)5 pathway has recently been explored for providing putative survival signals to CML stem/progenitor cells (SPCs) with contradictory results. We investigated the role of this pathway using the JAK2 inhibitor, ruxolitinib (RUX). We demonstrated that the combination of RUX, at clinically achievable concentrations, with the specific and potent tyrosine kinase inhibitor nilotinib, reduced the activity of the JAK2/STAT5 pathway in vitro relative to either single agent alone. These effects correlated with increased apoptosis of CML SPCs in vitro and a reduction in primitive quiescent CML stem cells, including NOD.Cg-Prkdc(scid) IL2rg(tm1Wjl) /SzJ mice repopulating cells, induced by combination treatment. A degree of toxicity toward normal SPCs was observed with the combination treatment, although this related to mature B-cell engraftment in NOD.Cg-Prkdc(scid) IL2rg(tm1Wjl) /SzJ mice with minimal effects on primitive CD34(+) cells. These results support the JAK2/STAT5 pathway as a relevant therapeutic target in CML SPCs and endorse the current use of nilotinib in combination with RUX in clinical trials to eradicate persistent disease in CML patients.
authors: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary & Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom;
authors: Paolo
authors: P
authors: Gallipoli
authors: Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute, City of Hope Cancer Center, Duarte, CA; and.
authors: Amy
authors: A
authors: Cook
authors: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary & Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom;
authors: Susan
authors: S
authors: Rhodes
authors: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary & Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom;
authors: Lisa
authors: L
authors: Hopcroft
authors: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary & Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom;
authors: Helen
authors: H
authors: Wheadon
authors: Stem Cell and Leukemia Proteomics Laboratory, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom.
authors: Anthony D
authors: AD
authors: Whetton
authors: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary & Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom;
authors: Heather G
authors: HG
authors: Jørgensen
authors: Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute, City of Hope Cancer Center, Duarte, CA; and.
authors: Ravi
authors: R
authors: Bhatia
authors: Paul O'Gorman Leukaemia Research Centre, College of Medical, Veterinary & Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom;
authors: Tessa L
authors: TL
authors: Holyoake
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009570:Nitriles; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D018952:Antigens, CD34; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; C540383:ruxolitinib; D016044:Fusion Proteins, bcr-abl; C507924:JAK2 protein, human; D053614:Janus Kinase 2; C498826:nilotinib