Chen Wen-Lian, Wang Jing-Han, Zhao Ai-Hua, Xu Xin, Wang Yi-Huang, Chen Tian-Lu, Li Jun-Min, Mi Jian-Qing, Zhu Yong-Mei, Liu Yuan-Fang, Wang Yue-Ying, Jin Jie, Huang He, Wu De-Pei, Li Yan, Yan Xiao-Jing, Yan Jin-Song, Li Jian-Yong, Wang Shuai, Huang Xiao-Jun, Wang Bing-Shun, Chen Zhu, Chen Sai-Juan, Jia Wei
Key Laboratory of Systems Biomedicine of Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University (SJTU) and State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, SJTU School of Medicine, Shanghai, China; Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China;
Key Laboratory of Systems Biomedicine of Ministry of Education, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University (SJTU) and State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, SJTU School of Medicine, Shanghai, China;
Blood. 2014 Sep 4;124(10):1645-54. doi: 10.1182/blood-2014-02-554204. Epub 2014 Jul 8.
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 tricarboxylic [corrected] 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.
急性髓系白血病（AML）是一组具有高度异质性的血液系统恶性肿瘤。利用分子生物标志物来改善AML患者（包括细胞遗传学正常的患者）的风险分层的需求日益增加。在此，我们报告一项代谢组学研究，该研究在400例AML患者和446例健康对照中鉴定出一种独特的葡萄糖代谢特征。该葡萄糖代谢特征由一组6种血清代谢物标志物组成，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为每位患者生成了一个包含6种代谢物标志物的预后风险评分（PRS）。低PRS能够独立于已确立的标志物预测生存不良的患者。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种代谢物标志物的代谢途径密切相关，低PRS组在基因表达水平上糖酵解和三羧酸循环增强。体外结果表明，糖酵解增强导致对抗白血病药物阿糖胞苷（Ara-C）的敏感性降低，而抑制糖酵解则抑制AML细胞增殖并增强Ara-C的细胞毒性。我们的研究为使用血清代谢物和代谢途径作为AML的新型预后标志物和潜在治疗靶点提供了有力证据。
