Zhang, B., Chu, S., Agarwal, P., Campbell, V. L., Hopcroft, L. , Jørgensen, H. G., Lin, A., Gaal, K., Holyoake, T. L. and Bhatia, R. (2016) Inhibition of interleukin-1 signaling enhances elimination of tyrosine kinase inhibitor treated CML stem cells. Blood, 128(23), pp. 2671-2682. (doi:10.1182/blood-2015-11-679928) (PMID:27621307) (PMCID:PMC5146743)
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Abstract
Treatment of chronic myelogenous leukemia (CML) with BCR-ABL tyrosine kinase inhibitors (TKI) fails to eliminate leukemia stem cells (LSC). Patients remain at risk for relapse, and additional approaches to deplete CML LSC are needed to enhance the possibility of discontinuing TKI treatment. We have previously reported that expression of the pivotal proinflammatory cytokine interleukin-1 (IL-1) is increased in CML bone marrow (BM). We show here that CML LSC demonstrated increased expression of the IL-1 receptors, IL-1RAP and IL- 1R1, and enhanced sensitivity to IL-1-induced NF-KB signaling compared to normal stem cells. Treatment with recombinant IL-1 receptor antagonist (IL-1RA) inhibited IL-1 signaling in CML LSC and inhibited growth of CML LSC. Importantly, the combination of IL-1RA with TKI resulted in significantly greater inhibition of CML LSC compared with TKI alone. Our studies also suggest that IL-1 signaling contributes to overexpression of inflammatory mediators in CML LSC, suggesting that blocking IL-1 signaling could modulate the inflammatory milieu. We conclude that IL-1 signaling contributes to maintenance of CML LSC following TKI treatment, and that IL- 1 blockade with IL-1RA enhances elimination of TKI-treated CML LSC. These results provide a strong rationale for further exploration of anti-IL-1 strategies to enhance LSC elimination in CML.
| Item Type: | Articles |
|---|---|
| Additional Information: | This work was supported by National Institutes of Health, National Cancer Institute grant R01 CA172447, the Glasgow Experimental Cancer Medicine Centre, Bloodwise grant 14033, and Cancer Research-UK program grant C1107/A11008. V.L.C. is supported by the Wellcome Trust, the Scottish Translational Medicine, and Therapeutics Initiative (grant WT 085664) and by Clinical Research Fellowship Number 099710/X/12/Z. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Holyoake, Professor Tessa and Campbell, Dr Victoria and Jorgensen, Dr Heather and Hopcroft, Dr Lisa |
| Authors: | Zhang, B., Chu, S., Agarwal, P., Campbell, V. L., Hopcroft, L., Jørgensen, H. G., Lin, A., Gaal, K., Holyoake, T. L., and Bhatia, R. |
| 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 |
| Published Online: | 12 September 2016 |
| Copyright Holders: | Copyright © 2016 American Society of Hematology |
| First Published: | First published in Blood 128(23):2671-2682 |
| Publisher Policy: | Reproduced in accordance with the copyright policy of the publisher |
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