Quantitative Proteomic Analysis of Plasma Exosomes to Identify the Candidate Biomarker of Imatinib Resistance in Chronic Myeloid Leukemia Patients.
Quantitative Proteomic Analysis of Plasma Exosomes to Identify the Candidate Biomarker of Imatinib Resistance in Chronic Myeloid Leukemia Patients.
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血浆外泌体的定量蛋白质组学分析，以确定慢性粒细胞白血病患者伊马替尼耐药的候选生物标志物
DOI：
10.3389/fonc.2021.779567
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发表时间：
2021
影响因子：
4.7
通讯作者：
Huang B
中科院分区：
文献类型：
--
作者：
Li MY;Zhao C;Chen L;Yao FY;Zhong FM;Chen Y;Xu S;Jiang JY;Yang YL;Min QH;Lin J;Zhang HB;Liu J;Wang XZ;Huang B
背景：酪氨酸激酶抑制剂伊马替尼(Imatinib，IM)可显著改善慢性粒细胞白血病(CML)患者的生存时间和生活质量。然而，缺乏IM耐药的特异性生物标志物仍然是一个严重的临床挑战。近年来，越来越多的证据表明，含外切体的蛋白质与肿瘤耐药有关，有望成为肿瘤诊断和药物敏感性预测的新型生物标志物。因此，我们旨在研究慢性粒细胞白血病患者血浆外切体的蛋白质组学特征，以寻找理想的IM抵抗的生物标志物。方法采用超速离心法从9例伊马替尼耐药和9例伊马替尼敏感的CML患者的混合血浆中提取外切体。然后，我们用基于LC-MS/MS的无标记定量技术来鉴定外体蛋白的表达水平。采用生物信息学方法对蛋白质组数据进行分析。最后，应用蛋白质印迹(WB)和平行反应监测(PRM)分析对候选蛋白质进行验证。结果在伊马替尼耐药和伊马替尼敏感的慢性粒细胞白血病患者血浆外切体中共鉴定出2812个蛋白质，其中279个差异表达蛋白质(DEP)符合限制性标准(折叠式改变≥1.5或≤0.667，p<；0.05)。与伊马替尼敏感的CML患者相比，151个蛋白表达上调，128个蛋白表达下调。生物信息学分析表明，上调的蛋白质主要是调节蛋白质的合成，而下调的蛋白质主要参与脂类代谢。前20个HUB基因是使用STRING和Cytoscape获得的，其中大部分是核糖体的组成部分。此外，我们发现RPL13和RPL14在对伊马替尼耐药的CML患者中表现出异常的上调，这一点得到了PRM和WB的进一步证实。结论血浆外切体蛋白质组学分析为研究慢性粒细胞白血病IM耐药提供了新的思路和重要信息。尤其是胞外体蛋白(RPL13和RPL14)，它们可能是IM抗性的潜在生物标志物。
Background Imatinib (IM), a tyrosine kinase inhibitor (TKI), has markedly improved the survival and life quality of chronic myeloid leukemia (CML) patients. However, the lack of specific biomarkers for IM resistance remains a serious clinical challenge. Recently, growing evidence has suggested that exosome-harbored proteins were involved in tumor drug resistance and could be novel biomarkers for the diagnosis and drug sensitivity prediction of cancer. Therefore, we aimed to investigate the proteomic profile of plasma exosomes derived from CML patients to identify ideal biomarkers for IM resistance. Methods We extracted exosomes from pooled plasma samples of 9 imatinib-resistant CML patients and 9 imatinib-sensitive CML patients by ultracentrifugation. Then, we identified the expression levels of exosomal proteins by liquid chromatography-tandem mass spectrometry (LC-MS/MS) based label free quantification. Bioinformatics analyses were used to analyze the proteomic data. Finally, the western blot (WB) and parallel reaction monitoring (PRM) analyses were applied to validate the candidate proteins. Results A total of 2812 proteins were identified in plasma exosomes from imatinib-resistant and imatinib-sensitive CML patients, including 279 differentially expressed proteins (DEPs) with restricted criteria (fold change≥1.5 or ≤0.667, p<0.05). Compared with imatinib-sensitive CML patients, 151 proteins were up-regulated and 128 proteins were down-regulated. Bioinformatics analyses revealed that the main function of the upregulated proteins was regulation of protein synthesis, while the downregulated proteins were mainly involved in lipid metabolism. The top 20 hub genes were obtained using STRING and Cytoscape, most of which were components of ribosomes. Moreover, we found that RPL13 and RPL14 exhibited exceptional upregulation in imatinib-resistant CML patients, which were further confirmed by PRM and WB. Conclusion Proteomic analysis of plasma exosomes provides new ideas and important information for the study of IM resistance in CML. Especially the exosomal proteins (RPL13 and RPL14), which may have great potential as biomarkers of IM resistance.
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DOI：
10.1056/nejmoa1609324
发表时间：
2017-03-09
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hochhaus A;Larson RA;Guilhot F;Radich JP;Branford S;Hughes TP;Baccarani M;Deininger MW;Cervantes F;Fujihara S;Ortmann CE;Menssen HD;Kantarjian H;O'Brien SG;Druker BJ;IRIS Investigators
通讯作者：
IRIS Investigators
DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
靶向 USP47 克服酪氨酸激酶抑制剂耐药性并根除慢性粒细胞白血病中的白血病干/祖细胞
影响因子：
16.6
作者：
Lei H;Xu HZ;Shan HZ;Liu M;Lu Y;Fang ZX;Jin J;Jing B;Xiao XH;Gao SM;Gao FH;Xia L;Yang L;Liu LG;Wang WW;Liu CX;Tong Y;Wu YZ;Zheng JK;Chen GQ;Zhou L;Wu YL
通讯作者：
Wu YL
SLE非编码遗传风险变异决定了控制疾病关键microRNA表达的免疫细胞特异性增强子的表观遗传功能障碍
影响因子：
16.6
作者：
Hou G;Harley ITW;Lu X;Zhou T;Xu N;Yao C;Qin Y;Ouyang Y;Ma J;Zhu X;Yu X;Xu H;Dai D;Ding H;Yin Z;Ye Z;Deng J;Zhou M;Tang Y;Namjou B;Guo Y;Weirauch MT;Kottyan LC;Harley JB;Shen N
通讯作者：
Shen N
影响因子：
56.9
作者：
Ebright, Richard Y.;Lee, Sooncheol;Micalizzi, Douglas S.
通讯作者：
Micalizzi, Douglas S.