A distinct glucose metabolism signature of acute myeloid leukemia with prognostic value
A distinct glucose metabolism signature of acute myeloid leukemia with prognostic value
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DOI：
10.1182/blood-2014-02-554204
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发表时间：
2014-09-04
期刊：
影响因子：
20.3
通讯作者：
Jia, Wei
中科院分区：
文献类型：
--
作者：
Chen, Wen-Lian;Wang, Jing-Han;Jia, Wei
急性髓系白血病（acute myeloid leukemia，AML）是一组高度异质性的血液系统恶性肿瘤。越来越需要使用分子生物标志物改善AML患者的风险分层，包括具有正常细胞遗传学的患者。在这里，我们报告了一项代谢组学研究，该研究确定了400名AML患者和446名健康对照的独特葡萄糖代谢特征。葡萄糖代谢特征包括一组6种血清代谢物标志物，其在细胞遗传学正常的AML患者中显示出预后价值。我们使用主成分分析法为每例患者生成了6种代谢物标记物的预后风险评分（PRS）。较低的PRS能够独立于成熟的标志物预测患者的生存率。我们进一步比较了低PRS组和高PRS组AML原始细胞的基因表达模式，其与涉及6种代谢物标记物的代谢途径相关性良好，在低PRS组中，在基因表达水平上糖酵解和三氯乙酸循环增强。体外实验结果表明，糖酵解的增强有助于降低抗白血病药物阿糖胞苷（Ara-C）的敏感性，而抑制糖酵解抑制AML细胞增殖和增强Ara-C的细胞毒性。我们的研究为血清代谢物和代谢途径作为AML新的预后标志物和潜在的治疗靶点提供了强有力的证据。
Acute myeloid leukemia (AML) is a group of hematological malignancies with high heterogeneity. There is an increasing need to improve the risk stratification of AML patients, including those with normal cytogenetics, using molecular biomarkers. Here, we report a metabolomics study that identified a distinct glucose metabolism signature with 400 AML patients and 446 healthy controls. The glucose metabolism signature comprises a panel of 6 serum metabolite markers, which demonstrated prognostic value in cytogenetically normal AML patients. We generated a prognosis risk score (PRS) with 6 metabolite markers for each patient using principal component analysis. A low PRS was able to predict patients with poor survival independently of well-established markers. We further compared the gene expression patterns of AML blast cells between low and high PRS groups, which correlated well to the metabolic pathways involving the 6 metabolite markers, with enhanced glycolysis and trichloracetic acid cycle at gene expression level in low PRS group. In vitro results demonstrated enhanced glycolysis contributed to decreased sensitivity to antileukemic agent arabinofuranosyl cytidine (Ara-C), whereas inhibition of glycolysis suppressed AML cell proliferation and potentiated cytotoxicity of Ara-C. Our study provides strong evidence for the use of serum metabolites and metabolic pathways as novel prognostic markers and potential therapeutic targets for AML.