Valencia A, Román-Gómez J, Cervera J, Such E, Barragán E, Bolufer P, Moscardó F, Sanz G F, Sanz M A
Department of Hematology, Hospital Universitario La Fe, Valencia, Spain.
Leukemia. 2009 Sep;23(9):1658-66. doi: 10.1038/leu.2009.86. Epub 2009 Apr 23.
Activation of the Wnt signaling pathway has been implicated recently in the pathogenesis of leukemia. We studied the function of epigenetic regulation of the Wnt pathway and its prognostic relevance in acute myelogenous leukemia (AML). We used a methylation-specific polymerase chain reaction approach to analyze the promoter methylation status of a panel of Wnt antagonists including sFRP1, sFRP2, sFRP4, sFRP5, DKK1 and DKK3. Aberrant methylation of Wnt antagonists was detected in four AML cell lines and in up to 64% of AML marrow samples. Treatment of the cell lines with 5-aza-2'-deoxycytidine induced reexpression of methylated Wnt antagonists and inactivation of the Wnt pathway by downregulating the Wnt pathway genes cyclin D1, TCF1 and LEF1 and reducing nuclear localization of beta-catenin. In a subgroup of patients 60 years and younger with newly diagnosed AML and intermediate-risk cytogenetics, abnormal methylation of Wnt antagonists was associated with decreased 4-year relapse-free survival (28 vs 61%, respectively, P=0.03). Our results indicate a function of the epigenetic regulation of the Wnt pathway in predicting relapse in a subgroup of AML patients.
Wnt信号通路的激活最近被认为与白血病的发病机制有关。我们研究了Wnt通路的表观遗传调控功能及其在急性髓性白血病（AML）中的预后相关性。我们使用甲基化特异性聚合酶链反应方法分析了一组Wnt拮抗剂（包括sFRP1、sFRP2、sFRP4、sFRP5、DKK1和DKK3）的启动子甲基化状态。在四种AML细胞系以及高达64%的AML骨髓样本中检测到Wnt拮抗剂的异常甲基化。用5-氮杂-2'-脱氧胞苷处理细胞系可诱导甲基化的Wnt拮抗剂重新表达，并通过下调Wnt通路基因细胞周期蛋白D1、TCF1和LEF1以及减少β-连环蛋白的核定位来使Wnt通路失活。在60岁及以下新诊断的AML且具有中危细胞遗传学特征的患者亚组中，Wnt拮抗剂的异常甲基化与4年无复发生存率降低相关（分别为28%和61%，P = 0.03）。我们的结果表明Wnt通路的表观遗传调控在预测一部分AML患者的复发中具有作用。
