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

Treatment of chronic myeloid leukemia (CML) with imatinib mesylate and other second/third generation c-Abl specific tyrosine kinase inhibitors (TKIs) has significantly extended patient survival 1 . However, TKIs primarily target differentiated cells and do not eliminate leukemic stem cells (LSCs) 2...

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Veröffentlicht in:Nature medicine 2017-09, Vol.23 (10), p.1234-1240
Hauptverfasser: Kuntz, Elodie M., Baquero, Pablo, Michie, Alison M., Dunn, Karen, Tardito, Saverio, Holyoake, Tessa L., Helgason, G. Vignir, Gottlieb, Eyal
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Sprache:eng
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Zusammenfassung:Treatment of chronic myeloid leukemia (CML) with imatinib mesylate and other second/third generation c-Abl specific tyrosine kinase inhibitors (TKIs) has significantly extended patient survival 1 . However, TKIs primarily target differentiated cells and do not eliminate leukemic stem cells (LSCs) 2 – 4 . Therefore, targeting minimal residual disease, to prevent acquired resistance and/or disease relapse requires identification of novel LSC-selective target(s) that can be exploited therapeutically 5 , 6 . Given that malignant transformation involves cellular metabolic changes, which may in turn render the transformed cells susceptible to specific assaults in a selective manner 7 , we searched for such vulnerabilities in CML LSCs. We performed metabolic analyses on both stem cell-enriched (CD34 + and CD34 + CD38 - ) and differentiated (CD34 - ) patient derived CML cells, and compared their signature with that of normal counterparts. Combining 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 of imatinib with 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 indication for investigating the employment of TKIs in combination with tigecycline to treat CML patients with minimal residual disease.
ISSN:1078-8956
1546-170X
DOI:10.1038/nm.4399