Department of Internal Medicine III, University of Ulm, Ulm, Germany.
Blood. 2010 Jan 21;115(3):636-42. doi: 10.1182/blood-2009-03-211003. Epub 2009 Nov 10.
Acute myeloid leukemia (AML) is characterized by molecular heterogeneity that is not fully reflected in the current classification system. Recent insights point toward a significant role of aberrant DNA methylation in leukemogenesis. Therefore, we investigated the prognostic impact of DNA methylation in AML. To screen for promoter methylation in AML we applied a combination of base-specific cleavage biochemistry and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), a powerful methodology allowing for quantitatively investigating DNA methylation status in a large series of both promoter regions and leukemia samples. We analyzed 92 genomic regions in 182 patient samples, correlated findings with clinical and molecular data, and validated the results in an independent cohort of 74 AML samples. Using this approach, we were able to identify novel leukemia subgroups based on distinct DNA methylation patterns. Furthermore, we defined a methylation-based outcome predictor for patient survival (P < .01) that in multivariable analysis provided independent prognostic information (hazard ratio, 1.52; 95% CI, 1.06-2.16). Here, we report the first large-scale methylation-based outcome predictor in AML, and thereby our findings support the use of genomic methylation markers for improved molecular classification and prognostication in adult AML.
急性髓系白血病 (AML) 的特征是分子异质性，而这在当前的分类系统中并未得到充分反映。最近的研究结果表明，异常的 DNA 甲基化在白血病发生中起着重要作用。因此，我们研究了 AML 中 DNA 甲基化的预后影响。为了筛选 AML 中的启动子甲基化，我们应用了碱基特异性切割生物化学和基质辅助激光解吸/电离飞行时间质谱 (MALDI-TOF-MS) 的组合，这是一种强大的方法，可定量研究大量启动子区域和白血病样本中的 DNA 甲基化状态。我们分析了 182 个患者样本中的 92 个基因组区域，将发现与临床和分子数据相关联，并在 74 个 AML 样本的独立队列中验证了结果。使用这种方法，我们能够根据不同的 DNA 甲基化模式识别出新的白血病亚群。此外，我们定义了一个基于甲基化的患者生存预后预测因子 (P <.01)，在多变量分析中提供了独立的预后信息 (风险比，1.52；95%CI，1.06-2.16)。在这里，我们报告了 AML 中第一个基于大规模甲基化的预后预测因子，因此我们的研究结果支持使用基因组甲基化标记来改善成人 AML 的分子分类和预后预测。
