Targeting quiescent leukemic stem cells using second generation autophagy inhibitors

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 Gottlieb, Professor Eyal and Halsey, Dr Christina and Mitchell, Dr Rebecca and Baquero, Dr Pablo and Olivares, Miss Orianne and Michie, Dr Alison and Kuntz, Elodie Marie and Helgason, Dr Vignir and Holyoake, Professor Tessa and Ianniciello, Angela 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 > Institute 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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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
647981CR-UK Centre renewalKaren VousdenCancer Research UK (CRUK)18076RI CANCER SCIENCES
600561MICA: Determining the therapeutic potential of targeting mTORC-1/2 in chronic lymphocytic leukaemia - a pre-clinical studyAlison MichieMedical Research Council (MRC)MR/K014854/1ICS - PAUL O'GORMAN LEUKAEMIA RESEARCH C
542691Development of a flow cytometry service within the Paul O'Gorman Leukaemia Research CentreAlison MichieThe Kay Kendall Leukaemia Fund (KENDALL)KKL501RI CANCER SCIENCES
608811Autophagy Inhibition Combined with Targeted Therapy for Elimination of CML Stem Cells.Vignir HelgasonThe Kay Kendall Leukaemia Fund (KENDALL)KKL698RI CANCER SCIENCES
722281Identifying and Targeting Metabolic Dependencies in Tyrosine Kinase-Driven Myeloid LeukaemiasVignir HelgasonThe Kay Kendall Leukaemia Fund (KENDALL)KKL1069RI CANCER SCIENCES
679891Targeting p53, cMyc and PRC2 regulatory hubs: A systematic and stratified approach to deliver new therapeutics for CMLDavid VetrieBloodwise (BLOODWIS)14033ICS - EPIGENETICS