Structural Biology Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain.
Leukemia. 2010 Apr;24(4):788-97. doi: 10.1038/leu.2009.295. Epub 2010 Jan 21.
Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease exhibiting variable clinical course and survival rates. Mutational status of the immunoglobulin heavy chain variable regions (IGHVs) of CLL cells offers useful prognostic information for high-risk patients, but time and economical costs originally prevented it from being routinely used in a clinical setting. Instead, alternative markers of IGHV status, such as zeta-associated protein (ZAP70) or messenger RNA levels are often used. We report a (1)H-NMR-based metabolomics approach to examine serum metabolic profiles of early stage, untreated CLL patients (Binet stage A) classified on the basis of IGHV mutational status or ZAP70. Metabolic profiles of CLL patients (n=29) exhibited higher concentrations of pyruvate and glutamate and decreased concentrations of isoleucine compared with controls (n=9). Differences in metabolic profiles between unmutated (UM-IGHV; n=10) and mutated IGHV (M-IGHV; n=19) patients were determined using partial least square discriminatory analysis (PLS-DA; R(2)=0.74, Q(2)=0.36). The UM-IGHV patients had elevated levels of cholesterol, lactate, uridine and fumarate, and decreased levels of pyridoxine, glycerol, 3-hydroxybutyrate and methionine concentrations. The PLS-DA models derived from ZAP70 classifications showed comparatively poor goodness-of-fit values, suggesting that IGHV mutational status correlates better with disease-related metabolic profiles. Our results highlight the usefulness of (1)H-NMR-based metabolomics as a potential non-invasive prognostic tool for identifying CLL disease-state biomarkers.
慢性淋巴细胞白血病（CLL）是一种异质性疾病，表现出不同的临床过程和生存率。CLL 细胞免疫球蛋白重链可变区（IGHVs）的突变状态为高危患者提供了有用的预后信息，但最初由于时间和经济成本的限制，无法在临床环境中常规使用。相反，IGHV 状态的替代标志物，如ζ相关蛋白（ZAP70）或信使 RNA 水平，通常被使用。我们报告了一种基于 1H-NMR 的代谢组学方法，用于检查根据 IGHV 突变状态或 ZAP70 分类的早期、未经治疗的 CLL 患者（Binet 阶段 A）的血清代谢谱。与对照组（n=9）相比，CLL 患者（n=29）的代谢谱表现出较高的丙酮酸和谷氨酸浓度以及较低的异亮氨酸浓度。使用偏最小二乘判别分析（PLS-DA；R2=0.74，Q2=0.36）确定未突变（UM-IGHV；n=10）和突变 IGHV（M-IGHV；n=19）患者之间的代谢谱差异。UM-IGHV 患者的胆固醇、乳酸、尿苷和延胡索酸水平升高，吡哆醇、甘油、3-羟基丁酸和蛋氨酸浓度降低。来自 ZAP70 分类的 PLS-DA 模型显示出相对较差的拟合优度值，表明 IGHV 突变状态与疾病相关的代谢谱相关性更好。我们的结果强调了基于 1H-NMR 的代谢组学作为一种潜在的非侵入性预后工具，用于识别 CLL 疾病状态生物标志物的有用性。
