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

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 survival1. However, TKIs primarily target differentiated cells and do not eliminate leukemic stem cells (LSCs)2,3,4. 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 therapeutically5,6. Considering that malignant transformation involves cellular metabolic changes, which may in turn render the transformed cells susceptible to specific assaults in a selective manner7, 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.

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Figure 1: Primitive CML cells show an increase in oxidative metabolism as compared to differentiated counterparts.
Figure 2: Mitochondrial metabolic activity is enhanced in primitive CML cells in comparison to normal undifferentiated hematopoietic cells.
Figure 3: Inhibition of aberrant oxidative metabolism targets CML progenitors and LSCs.
Figure 4: Inhibition of oxidative metabolism eliminates xenotransplanted human CML LSCs.

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Acknowledgements

The authors would like to dedicate this work to the memory of Prof. Tessa Holyoake who sadly passed away recently. Tessa was a dedicated clinician and an enthusiastic scientist who combined both aspects of her work for patients' benefit. She will be gravely missed.

We thank all patients and healthy donors who contributed samples and National Health Service (NHS) Greater Glasgow and Clyde Biorepository; A. Hair for sample processing; T. Gilbey and T. Harvey for cell sorting; N. Van Den Broek and G. MacKay for technical assistance; and A. King for editorial work. This study was supported by Cancer Research UK; the Cancer ResearchUK Glasgow Centre (C596/A18076) and the Biological Services Unit facilities at the Cancer Research UK Beatson Institute (C596/A17196); Medical Research Council/AstraZeneca project grants (MR/K014854/1); the Glasgow Experimental Cancer Medicine Centre (ECMC), which is funded by Cancer Research UK and by the Chief Scientist's Office (Scotland); the Howat Foundation and Friends of Paul O'Gorman; the Bloodwise Specialist Programme (14033); the Kay Kendall Leukaemia Fund (KKLF) (KKL501 and KKL698); Lady Tata International Award; and Leuka. G.V.H. is a KKLF Intermediate Research Fellow, Leadership Fellow and John Goldman Fellow.

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Contributions

E.M.K., G.V.H. and E.G. wrote the manuscript. E.M.K., P.B., T.L.H., G.V.H. and E.G. designed experiments and interpreted data. E.M.K. and P.B. performed experiments and analyzed data. A.M.M. and K.D. assisted with the in vivo work. S.T. provided the custom-formulated culture medium. T.L.H. and G.V.H. provided primary cells. G.V.H. and E.G. supervised the project. All authors reviewed the manuscript.

Corresponding authors

Correspondence to G Vignir Helgason or Eyal Gottlieb.

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Competing interests

E.G. is a founder and shareholder of MetaboMed, Ltd. T.L.H. has previously received research support from Bristol-Myers Squibb and Novartis.

Supplementary information

Supplementary Figures

Supplementary Figures 1–8. (PDF 39660 kb)

Life Sciences Reporting Summary (PDF 207 kb)

Supplementary Table 1

Comparative steady-state metabolomics analysis of patient-matched CD34+ and CD34 CML cells measured by LC–MS. (XLSX 18 kb)

Supplementary Table 2

Comparative steady-state metabolomics analysis of CD34+ CML and normal CD34+ cells measured by LC–MS. (XLSX 16 kb)

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Kuntz, E., Baquero, P., Michie, A. et al. Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells. Nat Med 23, 1234–1240 (2017). https://doi.org/10.1038/nm.4399

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