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

Abstract

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.