Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells.
Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells.
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DOI：
10.1038/nm.4399
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发表时间：
2017-10
期刊：
影响因子：
82.9
通讯作者：
Gottlieb E
中科院分区：
文献类型：
--
作者：
Kuntz EM;Baquero P;Michie AM;Dunn K;Tardito S;Holyoake TL;Helgason GV;Gottlieb E
用甲磺酸伊马替尼和其他第二/第三代c-Abl特异性酪氨酸激酶抑制剂（TKI）治疗慢性髓性白血病（CML）显著延长了患者生存期。然而，TKI主要靶向分化的细胞，并且不消除白血病干细胞（LSC）。因此，靶向微小残留病以预防获得性耐药性和/或疾病复发需要鉴定可在治疗上利用的新型LSC选择性靶标。鉴于恶性转化涉及细胞代谢变化，这反过来可能使转化的细胞以选择性的方式对特定的攻击敏感，我们在CML LSC中寻找这种脆弱性。我们对干细胞富集（CD 34+和CD 34 + CD 38-）和分化（CD 34-）患者来源的CML细胞进行了代谢分析，并将其特征与正常对应物进行了比较。结合稳定的同位素辅助代谢组学与功能测定，我们证明了原始CML细胞依赖于上调的氧化代谢的生存。我们还表明，伊马替尼与替加环素（一种抑制线粒体蛋白翻译的抗生素）联合治疗，在体外和人类CML异种移植模型中选择性根除CML LSC。我们的研究结果为研究TKI联合替加环素治疗微小残留病的CML患者提供了强有力的证据。
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. 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 novel LSC-selective target(s) that can be exploited therapeutically. Given 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-) 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.
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抑制线粒体翻译是人类急性髓样白血病的治疗策略。
影响因子：
50.3
作者：
Skrtić M;Sriskanthadevan S;Jhas B;Gebbia M;Wang X;Wang Z;Hurren R;Jitkova Y;Gronda M;Maclean N;Lai CK;Eberhard Y;Bartoszko J;Spagnuolo P;Rutledge AC;Datti A;Ketela T;Moffat J;Robinson BH;Cameron JH;Wrana J;Eaves CJ;Minden MD;Wang JC;Dick JE;Humphries K;Nislow C;Giaever G;Schimmer AD
通讯作者：
Schimmer AD
影响因子：
158.5
作者：
Druker, Brian J.;Guilhot, Francois;Larson, Richard A.
通讯作者：
Larson, Richard A.
影响因子：
64.5
作者：
GROFFEN, J;STEPHENSON, JR;GROSVELD, G
通讯作者：
GROSVELD, G
影响因子：
23.9
作者：
Yu, Wen-Mei;Liu, Xia;Shen, Jinhua;Jovanovic, Olga;Pohl, Elena E.;Gerson, Stanton L.;Finkel, Toren;Broxmeyer, Hal E.;Qu, Cheng-Kui
通讯作者：
Qu, Cheng-Kui
影响因子：
12.4
作者：
Norberg, Erik;Lako, Ana;Danial, Nika N.
通讯作者：
Danial, Nika N.