Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism.
Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism.
复制标题
DOI：
10.1158/2159-8290.cd-16-0441
复制
发表时间：
2017-07
期刊：
影响因子：
28.2
通讯作者：
Sarry JE
中科院分区：
文献类型：
--
作者：
Farge T;Saland E;de Toni F;Aroua N;Hosseini M;Perry R;Bosc C;Sugita M;Stuani L;Fraisse M;Scotland S;Larrue C;Boutzen H;Féliu V;Nicolau-Travers ML;Cassant-Sourdy S;Broin N;David M;Serhan N;Sarry A;Tavitian S;Kaoma T;Vallar L;Iacovoni J;Linares LK;Montersino C;Castellano R;Griessinger E;Collette Y;Duchamp O;Barreira Y;Hirsch P;Palama T;Gales L;Delhommeau F;Garmy-Susini BH;Portais JC;Vergez F;Selak M;Danet-Desnoyers G;Carroll M;Récher C;Sarry JE
化疗耐药的人急性髓系白血病(AML)细胞被认为富含静止的未成熟白血病干细胞(LSCs)。为了在体内验证这一假设，我们开发了一种临床相关的化疗方法，用阿糖胞苷治疗患者来源的异种移植(PDX)。阿糖胞苷残留的AML细胞既不在未成熟、静止的细胞中浓缩，也不在LSCs中浓缩。引人注目的是，对阿糖胞苷耐药的预先存在和持续存在的细胞显示出高水平的活性氧，表现出线粒体质量增加，并保留了活跃的极化线粒体，这与高氧化磷酸化(OXPHOS)状态一致。阿糖胞苷残留细胞表现为脂肪酸氧化增加，CD36表达上调，以及高OXPHOS基因签名预测PDX和AML患者的治疗反应。高OXPHOS而不是低OXPHOS的人AML细胞株在体内对化疗药物耐药。靶向线粒体蛋白质合成、电子转移或脂肪酸氧化诱导能量向低OXPHOS转变，并显著增强阿糖胞苷的抗白血病作用。总之，这项研究表明，基本的线粒体功能有助于急性髓细胞白血病对阿糖胞苷的耐药性，是阿糖胞苷敏感性的一个强有力的标志，也是治疗急性髓细胞白血病残留疾病的一种有前景的治疗途径。
Chemotherapy-resistant human acute myeloid leukemia (AML) cells are thought to be enriched in quiescent immature leukemic stem cells (LSCs). To validate this hypothesis in vivo, we developed a clinically relevant chemotherapeutic approach treating patient-derived xenograft (PDX) with cytarabine. Cytarabine residual AML cells are enriched neither in immature, quiescent cells nor LSCs. Strikingly, cytarabine-resistant pre-existing and persisting cells displayed high levels of reactive oxygen species, showed increased mitochondrial mass, and retained active polarized mitochondria, consistent with a high oxidative phosphorylation (OXPHOS) status. Cytarabine residual cells exhibited increased fatty acid oxidation, upregulated CD36 expression and a HIGH OXPHOS gene signature predictive for treatment response in PDX and AML patients. HIGH OXPHOS but not LOW OXPHOS human AML cell lines were chemoresistant in vivo. Targeting mitochondrial protein synthesis, electron transfer, or fatty acid oxidation induced an energetic shift towards LOW OXPHOS and markedly enhanced anti-leukemic effects of cytarabine. Together, this study demonstrates that essential mitochondrial functions contribute to cytarabine resistance in AML and are a robust hallmark of cytarabine sensitivity and a promising therapeutic avenue to treat AML residual disease.