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首页> 外文期刊>BMC Cancer >Prognostic significance and therapeutic potential of the activation of anaplastic lymphoma kinase/protein kinase B/mammalian target of rapamycin signaling pathway in anaplastic large cell lymphoma
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Prognostic significance and therapeutic potential of the activation of anaplastic lymphoma kinase/protein kinase B/mammalian target of rapamycin signaling pathway in anaplastic large cell lymphoma

机译：间变性大细胞淋巴瘤中间变性淋巴瘤激酶/蛋白激酶B /哺乳动物靶标雷帕霉素信号通路的活化的预后意义和治疗潜力

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Backgroud Activation of the protein kinase B/mammalian target of rapamycin (AKT/mTOR) pathway has been demonstrated to be involved in nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)-mediated tumorigenesis in anaplastic large cell lymphoma (ALCL) and correlated with unfavorable outcome in certain types of other cancers. However, the prognostic value of AKT/mTOR activation in ALCL remains to be fully elucidated. In the present study, we aim to address this question from a clinical perspective by comparing the expressions of the AKT/mTOR signaling molecules in ALCL patients and exploring the therapeutic significance of targeting the AKT/mTOR pathway in ALCL. Methods A cohort of 103 patients with ALCL was enrolled in the study. Expression of ALK fusion proteins and the AKT/mTOR signaling phosphoproteins was studied by immunohistochemical (IHC) staining. The pathogenic role of ALK fusion proteins and the therapeutic significance of targeting the ATK/mTOR signaling pathway were further investigated in vitro study with an ALK?+?ALCL cell line and the NPM-ALK transformed BaF3 cells. Results ALK expression was detected in 60% of ALCLs, of which 79% exhibited the presence of NPM-ALK, whereas the remaining 21% expressed variant-ALK fusions. Phosphorylation of AKT, mTOR, 4E-binding protein-1 (4E-BP1), and 70?kDa ribosomal protein S6 kinase polypeptide 1 (p70S6K1) was detected in 76%, 80%, 91%, and 93% of ALCL patients, respectively. Both phospho-AKT (p-AKT) and p-mTOR were correlated to ALK expression, and p-mTOR was closely correlated to p-AKT. Both p-4E-BP1 and p-p70S6K1 were correlated to p-mTOR, but were not correlated to the expression of ALK and p-AKT. Clinically, ALK?+?ALCL occurred more commonly in younger patients, and ALK?+?ALCL patients had a much better prognosis than ALK-ALCL cases. However, expression of p-AKT, p-mTOR, p-4E-BP1, or p-p70S6K1 did not have an impact on the clinical outcome. Overexpression of NPM-ALK in a nonmalignant murine pro-B lymphoid cell line, BaF3, induced the cells to become cytokine-independent and resistant to glucocorticoids (GCs). Targeting AKT/mTOR inhibited growth and triggered the apoptotic cell death of ALK?+?ALCL cells and NPM-ALK transformed BaF3 cells, and also reversed GC resistance induced by overexpression of NPM-ALK. Conclusions Overexpression of ALK due to chromosomal translocations is seen in the majority of ALCL patients and endows them with a much better prognosis. The AKT/mTOR signaling pathway is highly activated in ALK?+?ALCL patients and targeting the AKT/mTOR signaling pathway might confer a great therapeutic potential in ALCL.
机译：已经证明蛋白激酶B /哺乳动物雷帕霉素靶标（AKT / mTOR）途径的背景活化与间变性大细胞淋巴瘤（ALCL）的核蛋白-间变性淋巴瘤激酶（NPM-ALK）介导的肿瘤发生有关，且与不良相关在某些类型的其他癌症中的预后。但是，ALT中AKT / mTOR激活的预后价值仍有待充分阐明。在本研究中，我们旨在通过比较ALCL患者中AKT / mTOR信号分子的表达并探索在ALCL中靶向AKT / mTOR途径的治疗意义从临床角度解决此问题。方法纳入103例ALCL患者。通过免疫组织化学（IHC）染色研究了ALK融合蛋白和AKT / mTOR信号转导磷蛋白的表达。在ALKα+ΔALCL细胞系和NPM-ALK转化的BaF3细胞的体外研究中，进一步研究了ALK融合蛋白的致病作用和靶向ATK / mTOR信号通路的治疗意义。结果在60％的ALCL中检测到ALK表达，其中79％表现出NPM-ALK的存在，而其余21％则表达了变异的ALK融合。在76％，80％，91％和93％的ALCL患者中检测到AKT，mTOR，4E结合蛋白1（4E-BP1）和70？kDa核糖体蛋白S6激酶多肽1（p70S6K1）的磷酸化，分别。磷酸-AKT（p-AKT）和p-mTOR均与ALK表达相关，而p-mTOR与p-AKT密切相关。 p-4E-BP1和p-p70S6K1与p-mTOR相关，但与ALK和p-AKT的表达无关。临床上，ALKα+αALCL在年轻患者中更常见，并且ALKα+αALCL患者的预后要好于ALK-ALCL患者。但是，p-AKT，p-mTOR，p-4E-BP1或p-p70S6K1的表达对临床结果没有影响。 NPM-ALK在非恶性小鼠pro-B淋巴样细胞系BaF3中的过表达诱导细胞变得不依赖细胞因子并对糖皮质激素（GCs）具有抗性。靶向AKT / mTOR抑制生长并触发ALKα+ΔALCL细胞和NPM-ALK转化的BaF3细胞的凋亡细胞死亡，并且还逆转了由NPM-ALK的过表达诱导的GC抗性。结论在大多数ALCL患者中可见由于染色体易位引起的ALK过表达，并赋予他们更好的预后。 AKT / mTOR信号通路在ALKα+αALCL患者中被高度激活，靶向AKT / mTOR信号通路可能在ALCL中具有巨大的治疗潜力。

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