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.

中文翻译：

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靶向线粒体氧化磷酸化可根除耐药性慢性髓细胞白血病干细胞。

用甲磺酸伊马替尼和其他第二代和/或第三代 c-Abl 特异性酪氨酸激酶抑制剂 (TKI) 治疗慢性粒细胞白血病 (CML) 可显着延长患者的生存期。然而，TKI 主要针对分化细胞，不会消除白血病干细胞 (LSC)。因此，针对最小残留疾病以防止获得性耐药和/或疾病复发需要确定可用于治疗的新 LSC 选择性靶标。考虑到恶性转化涉及细胞代谢变化，这可能反过来使转化的细胞以选择性的方式易受特定攻击，我们在 CML LSCs 中寻找这种脆弱性。我们对富含干细胞的（CD34 ⁺和 CD34 ⁺CD38 ^- ) 和分化 (CD34 ^- ) 细胞来自 CML 个体，我们将这些细胞的特征与其正常对应细胞的特征进行了比较。通过将稳定同位素辅助代谢组学与功能测定相结合，我们证明原始 CML 细胞依赖于上调的氧化代谢来生存。我们还表明，伊马替尼和替加环素（一种抑制线粒体蛋白翻译的抗生素）的联合治疗可在体外和人类 CML 的异种移植模型中选择性地根除 CML LSC。我们的研究结果为研究使用 TKI 与替加环素联合治疗具有最小残留病的 CML 患者提供了强有力的理由。