Plasma exosomes as markers of therapeutic response in patients with acute myeloid leukemia.
Plasma exosomes as markers of therapeutic response in patients with acute myeloid leukemia.
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DOI：
10.3389/fimmu.2014.00160
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发表时间：
2014
影响因子：
7.3
通讯作者：
Boyiadzis M
中科院分区：
文献类型：
--
作者：
Hong CS;Muller L;Whiteside TL;Boyiadzis M
目的：从新诊断的急性髓性白血病（AML）患者的血浆中分离的外泌体具有升高的蛋白质和转化生长因子-β 1（TGF-β 1）含量并抑制自然杀伤（NK）细胞毒性（Haematologica 96，第1302页，2011）。在接受治疗的AML患者中评估了外泌体在预测对化疗（CT）的反应中的潜在作用。试验设计：从诊断时的AML患者（n = 16）、诱导后CT（n = 9）、巩固期CT（n = 10）、长期缓解期（Lt-CR，n = 5）和健康志愿者（n = 7）中获得血浆。通过尺寸排阻色谱和超离心分离外泌体。在患者队列中比较外泌体蛋白、可溶性TGF-β 1水平（ELISA）和TGF-β 1谱（Western印迹）。结果与患者的细胞遗传学特征、白血病原始细胞百分比和预后相关。结果：在诊断时，AML中的蛋白质和TGF-β 1水平高于对照外泌体（p <0.009和p <0.004）。这些值在诱导CT后降低（p <0.05和p <0.004），在巩固CT期间增加（p <0.02和p <0.005），并在Lt-CR中恢复正常。虽然TGF-β 1和蛋白质水平相互追踪，但在CT之前、期间和之后分离的TGF-β 1前肽、潜伏相关肽（LTP）或成熟TGF-β 1差异修饰外泌体。在对照组和Lt-CR患者的外泌体中仅观察到TGF-β 1前肽。在实变CT期间，外泌体携带TGF-β 1前肽、TGF-β 1和低水平的成熟TGF-β 1。NK细胞与携带所有三种TGF-β 1形式的AML外泌体共孵育诱导NKG2D表达下调。结论：外泌体蛋白和/或TGF-β 1含量的变化可能反映了CT的反应。外泌体特征可能提示在被认为已达到完全缓解的患者中存在残留疾病。
Purpose: Exosomes isolated from the plasma of newly diagnosed acute myeloid leukemia (AML) patients have elevated protein and transforming growth factor-beta 1 (TGF-β1) contents and inhibit natural killer (NK) cell cytotoxicity (Haematologica 96, p. 1302, 2011). A potential role of exosomes in predicting responses to chemotherapy (CT) was evaluated in AML patients undergoing treatment. Experimental Design: Plasma was obtained from AML patients at diagnosis (n = 16); post-induction CT (n = 9); during consolidation CT (n = 10); in long-term remission (Lt-CR, n = 5); and from healthy volunteers (n = 7). Exosomes were isolated by size-exclusion chromatography and ultracentrifugation. The exosomal protein, soluble TGFβ-1 levels (ELISA), and the TGF-β1 profiles (western blots) were compared among patients’ cohorts. The results were correlated with the patients’ cytogenetic profile, percentage of leukemic blast, and outcome. Results: At diagnosis, protein and TGF-β1 levels were higher (p < 0.009 and p < 0.004) in AML than control exosomes. These values decreased after induction CT (p < 0.05 and p < 0.004), increased during consolidation CT (p < 0.02 and p < 0.005), and normalized in Lt-CR. While TGF-β1 and protein levels tracked one another, TGF-β1 pro-peptide, latency-associated peptide (LAP), or mature TGF-β1 differentially decorated exosomes isolated before, during, and after CT. Only TGF-β1 pro-peptide was seen in exosomes of controls or Lt-CR patients. During consolidation CT, exosomes carried TGF-β1 pro-peptide, LAP, and low levels of mature TGF-β1. NK cell co-incubation with AML exosomes carrying all three TGF-β1 forms induced down-regulation of NKG2D expression. Conclusion: Changes in exosomal protein and/or TGF-β1 content may reflect responses to CT. The exosomal profile may suggest the presence of residual disease in patients considered to have achieved complete remission.
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