Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells

Kuntz, E. M., Baquero, P., Michie, A. M. , Dunn, K., Tardito, S. , Holyoake, T. L., Helgason, G. V. and Gottlieb, E. (2017) Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells. Nature Medicine, 23(10), pp. 1234-1240. (doi:10.1038/nm.4399) (PMID:28920959) (PMCID:PMC5657469)

Kuntz, E. M., Baquero, P., Michie, A. M. , Dunn, K., Tardito, S. , Holyoake, T. L., Helgason, G. V. and Gottlieb, E. (2017) Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells. Nature Medicine, 23(10), pp. 1234-1240. (doi:10.1038/nm.4399) (PMID:28920959) (PMCID:PMC5657469)

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Abstract

Treatment of chronic myeloid leukemia (CML) with imatinib mesylate and other second- and/or third-generation c-Abl-specific tyrosine kinase inhibitors (TKIs) has substantially extended patient survival. However, TKIs primarily target differentiated cells and do not eliminate leukemic stem cells (LSCs). Therefore, targeting minimal residual disease to prevent acquired resistance and/or disease relapse requires identification of new LSC-selective target(s) that can be exploited therapeutically. Considering that malignant transformation involves cellular metabolic changes, which may in turn render the transformed cells susceptible to specific assaults in a selective manner, we searched for such vulnerabilities in CML LSCs. We performed metabolic analyses on both stem cell-enriched (CD34(+) and CD34(+)CD38(-)) and differentiated (CD34(-)) cells derived from individuals with CML, and we compared the signature of these cells with that of their normal counterparts. Through combination of stable isotope-assisted metabolomics with functional assays, we demonstrate that primitive CML cells rely on upregulated oxidative metabolism for their survival. We also show that combination treatment with imatinib and tigecycline, an antibiotic that inhibits mitochondrial protein translation, selectively eradicates CML LSCs both in vitro and in a xenotransplantation model of human CML. Our findings provide a strong rationale for investigation of the use of TKIs in combination with tigecycline to treat patients with CML with minimal residual disease.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Tardito, Mr Saverio and Dunn, Mrs Karen and Michie, Dr Alison and Kuntz, Elodie Marie and Helgason, Dr Vignir and Holyoake, Professor Tessa and Gottlieb, Professor Eyal and Baquero, Dr Pablo
Authors: Kuntz, E. M., Baquero, P., Michie, A. M., Dunn, K., Tardito, S., Holyoake, T. L., Helgason, G. V., and Gottlieb, E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Nature Medicine
Publisher:Nature Publishing Group
ISSN:1078-8956
ISSN (Online):1546-170X
Published Online:18 September 2017
Copyright Holders:Copyright © 2017 Nature Publishing Group
First Published:First published in Nature Medicine 23(10):1234-1240
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
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