Mitochondrial oxidative phosphorylation is dispensable for survival of CD34(+) chronic myeloid leukemia stem and progenitor cells.
Mitochondrial oxidative phosphorylation is dispensable for survival of CD34(+) chronic myeloid leukemia stem and progenitor cells.
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线粒体氧化磷酸化对于CD34（+）慢性髓样白血病茎和祖细胞的存活是不可取的。
DOI：
10.1038/s41419-022-04842-5
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发表时间：
2022-04-20
影响因子：
9
通讯作者：
Lu, Ying
中科院分区：
文献类型：
--
作者：
Yan, Jin-Song;Yang, Meng-Ying;Zhang, Xue-Hong;Luo, Chen-Hui;Du, Cheng-Kan;Jiang, Yue;Dong, Xuan-Jia;Wang, Zhang-Man;Yang, Li-Xue;Li, Yi-Dong;Xia, Li;Lu, Ying
慢性粒细胞白血病 (CML) 由自我更新的恶性 CD34+ 干细胞引发和维持。人们在基因组学、转录组学和代谢组学研究中做出了大量努力来揭示白血病干/祖细胞的代谢特征。然而，很少进行蛋白质组学研究，并且关于代谢程序在什么水平上重新连接的机制仍然知之甚少。在这里，使用无标记定量蛋白质组学分析，我们将从 CML 个体收集的 CD34+ 干/祖细胞的特征与健康供体的特征进行比较，并观察到与有氧中央碳酸盐代谢途径相关的酶丰度的显着变化。具体而言，CML 干/祖细胞表达三羧酸循环 (TCA) 增加，糖酵解蛋白减少，并伴有氧化磷酸化 (OXPHOS) 增加和糖酵解活性降低。在体外和患者来源的肿瘤异种移植小鼠模型中，使用众所周知的 OXPHOS 抑制剂二甲双胍可根除 CML 干/祖细胞，并使 CD34+ CML 细胞对伊马替尼重新敏感。然而，与正常CD34+细胞不同的是，CML CD34+细胞中二甲双胍诱导的内质网应激使OXPHOS蛋白的丰度和活性均出乎意料地升高。相反，在 CML CD34+ 细胞中，二甲双胍下调了四种主要的异常表达蛋白组。这些数据挑战了 OXPHOS 对 CML CD34+ 细胞存活的依赖性，并强调了二甲双胍的新机制。更重要的是，它为酪氨酸激酶抑制剂联合二甲双胍治疗 CML 提供了强有力的理由。
Chronic myeloid leukemia (CML) are initiated and sustained by self-renewing malignant CD34+ stem cells. Extensive efforts have been made to reveal the metabolic signature of the leukemia stem/progenitor cells in genomic, transcriptomic, and metabolomic studies. However, very little proteomic investigation has been conducted and the mechanism regarding at what level the metabolic program was rewired remains poorly understood. Here, using label-free quantitative proteomic profiling, we compared the signature of CD34+ stem/progenitor cells collected from CML individuals with that of healthy donors and observed significant changes in the abundance of enzymes associated with aerobic central carbonate metabolic pathways. Specifically, CML stem/progenitor cells expressed increased tricarboxylic acid cycle (TCA) with decreased glycolytic proteins, accompanying by increased oxidative phosphorylation (OXPHOS) and decreased glycolysis activity. Administration of the well-known OXPHOS inhibitor metformin eradicated CML stem/progenitor cells and re-sensitized CD34+ CML cells to imatinib in vitro and in patient-derived tumor xenograft murine model. However, different from normal CD34+ cells, the abundance and activity of OXPHOS protein were both unexpectedly elevated with endoplasmic reticulum stress induced by metformin in CML CD34+ cells. The four major aberrantly expressed protein sets, in contrast, were downregulated by metformin in CML CD34+ cells. These data challenged the dependency of OXPHOS for CML CD34+ cell survival and underlined the novel mechanism of metformin. More importantly, it suggested a strong rationale for the use of tyrosine kinase inhibitors in combination with metformin in treating CML.
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影响因子：
50.3
作者：
Jones CL;Stevens BM;D'Alessandro A;Reisz JA;Culp-Hill R;Nemkov T;Pei S;Khan N;Adane B;Ye H;Krug A;Reinhold D;Smith C;DeGregori J;Pollyea DA;Jordan CT
通讯作者：
Jordan CT
DOI：
10.1038/nrm3772
发表时间：
2014-04
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.12717/dr.2017.21.2.139
发表时间：
2017-06
期刊：
Development & reproduction
影响因子：
--
作者：
Lee J;Park D;Lee Y
通讯作者：
Lee Y
影响因子：
82.9
作者：
Eppert, Kolja;Takenaka, Katsuto;Dick, John E.
通讯作者：
Dick, John E.
影响因子：
64.8
作者：
Hattori A;Tsunoda M;Konuma T;Kobayashi M;Nagy T;Glushka J;Tayyari F;McSkimming D;Kannan N;Tojo A;Edison AS;Ito T
通讯作者：
Ito T