Baquero, P. et al. (2019) Targeting quiescent leukemic stem cells using second generation autophagy inhibitors. Leukemia, 33(4), pp. 981-994. (doi: 10.1038/s41375-018-0252-4) (PMID:30185934) (PMCID:PMC6292500)
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Abstract
In chronic myeloid leukemia (CML), tyrosine kinase inhibitor (TKI) treatment induces autophagy that promotes survival and TKI-resistance in leukemic stem cells (LSCs). In clinical studies hydroxychloroquine (HCQ), the only clinically approved autophagy inhibitor, does not consistently inhibit autophagy in cancer patients, so more potent autophagy inhibitors are needed. We generated a murine model of CML in which autophagic flux can be measured in bone marrow-located LSCs. In parallel, we use cell division tracing, phenotyping of primary CML cells, and a robust xenotransplantation model of human CML, to investigate the effect of Lys05, a highly potent lysosomotropic agent, and PIK-III, a selective inhibitor of VPS34, on the survival and function of LSCs. We demonstrate that long-term haematopoietic stem cells (LT-HSCs: Lin−Sca-1+c-kit+CD48−CD150+) isolated from leukemic mice have higher basal autophagy levels compared with non-leukemic LT-HSCs and more mature leukemic cells. Additionally, we present that while HCQ is ineffective, Lys05-mediated autophagy inhibition reduces LSCs quiescence and drives myeloid cell expansion. Furthermore, Lys05 and PIK-III reduced the number of primary CML LSCs and target xenografted LSCs when used in combination with TKI treatment, providing a strong rationale for clinical use of second generation autophagy inhibitors as a novel treatment for CML patients with LSC persistence.
| Item Type: | Articles |
|---|---|
| Additional Information: | Also funded by the BSU facilities at the Cancer Research UK Beatson Institute (C596/A17196). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Dunn, Mrs Karen and Mukhopadhyay, Dr Arunima and Dawson, Ms Amy and Scott, Dr Mary and Ianniciello, Ms Angela and Gottlieb, Professor Eyal and Halsey, Professor Chris and Mitchell, Dr Rebecca and Baquero, Dr Pablo and Olivares, Miss Orianne and Michie, Professor Alison and Kuntz, Elodie Marie and Helgason, Professor Vignir and Holyoake, Professor Tessa and Ryan, Professor Kevin |
| Authors: | Baquero, P., Dawson, A., Mukhopadhyay, A., Kuntz, E. M., Mitchell, R., Olivares, O., Ianniciello, A., Scott, M. T., Dunn, K., Nicastri, M. C., Winkler, J. D., Michie, A. M., Ryan, K. M., Halsey, C., Gottlieb, E., Keaney, E. P., Murphy, L. O., Amaravadi, R. K., Holyoake, T. L., and Helgason, G. V. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing |
| Journal Name: | Leukemia |
| Publisher: | Nature Publishing Group |
| ISSN: | 0887-6924 |
| ISSN (Online): | 1476-5551 |
| Published Online: | 05 September 2018 |
| Copyright Holders: | Copyright © 2018 The Authors |
| First Published: | First published in Leukemia 33(4): 981-994 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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