JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of chronic phase CML CD34+ cells in vitro and in vivo

Gallipoli, P., Cook, A., Rhodes, S. , Hopcroft, L. , Wheadon, H. , Whetton, A. D., Jorgensen, H. G., Bhatia, R. and Holyoake, T. L. (2014) JAK2/STAT5 inhibition by nilotinib with ruxolitinib contributes to the elimination of chronic phase CML CD34+ cells in vitro and in vivo. Blood, 124(9), pp. 1492-1501. (doi:10.1182/blood-2013-12-545640) (PMID:24957147) (PMCID:PMC4148771)

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Abstract

Chronic myeloid leukaemia (CML) stem cell survival is not dependent on BCR-ABL protein kinase and treatment with ABL tyrosine kinase inhibitors (TKIs) cures only a minority of CML patients, thus highlighting the need for novel therapeutic targets. The JAK2/STAT5 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. We demonstrated that the combination of ruxolitinib, at clinically achievable concentrations, with the specific and potent TKI 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-<i>Prkdc<sup>scid</sup> IL2rg<sup>tm1Wjl</sup> /SzJ</i> mice (NSG) repopulating cells, induced by combination treatment. A degree of toxicity towards normal SPCs was observed with the combination treatment, although this related to mature B cell engraftment in NSG mice with minimal effects on primitive CD34<sup>+</sup> 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 ruxolitinib in clinical trials to eradicate persistent disease in CML patients.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Holyoake, Professor Tessa and Whetton, Prof Anthony and Gallipoli, Dr Paolo and Jorgensen, Dr Heather and Wheadon, Dr Helen and Rhodes, Dr Susan and Hopcroft, Dr Lisa
Authors: Gallipoli, P., Cook, A., Rhodes, S., Hopcroft, L., Wheadon, H., Whetton, A. D., Jorgensen, H. G., Bhatia, R., and Holyoake, T. L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Blood
Publisher:American Society of Hematology
ISSN:0006-4971
ISSN (Online):1528-0020
Copyright Holders:Copyright © 2014 American Society of Hematology
First Published:First published in Blood 124(9):1492-1501
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher.

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
540351The relevance of autocrine growth factor activation to the survival and proliferation of primitive chronic myeloid leukaemia (CML) cells.Paolo GallipoliMedical Research Council (MRC)G1000288RI CANCER SCIENCES
542691Development of a flow cytometry service within the Paul O'Gorman Leukaemia Research CentreAlison MichieThe Kay Kendall Leukaemia Fund (KENDALL)KKL501RI CANCER SCIENCES
637391Investigation of JAK2 targets is myeloproliferative disordersSusan RhodesScottish Executive Health Department (SEHHD-CSO)CAF/13/09RI CANCER SCIENCES
498551Key survival pathways in chronic myeloid leukaemia (cml) stem cells and novel approaches to their eradicationTessa HolyoakeCancer Research UK (CAN-RES-UK)11008RI CANCER SCIENCES
498552Key survival pathways in chronic myeloid leukaemia (cml) stem cells and novel approaches to their eradicationTessa HolyoakeCancer Research UK (CAN-RES-UK)11008RI CANCER SCIENCES