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, Professor 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 > School 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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