Román-Gómez José, Cordeu Lucia, Agirre Xabier, Jiménez-Velasco Antonio, San José-Eneriz Edurne, Garate Leire, Calasanz María José, Heiniger Anabel, Torres Antonio, Prosper Felipe
Department of Hematology, Hospital Reina Sofia, Cordoba, Spain.
Blood. 2007 Apr 15;109(8):3462-9. doi: 10.1182/blood-2006-09-047043. Epub 2006 Dec 5.
Activation of the Wnt/beta-catenin signaling pathway is a hallmark of a number of solid tumors. We analyzed the regulation of the Wnt/beta-catenin pathway in acute lymphoblastic leukemia (ALL) and its role in the pathogenesis of the disease. We found that expression of the Wnt inhibitors sFRP1, sFRP2, sFRP4, sFRP5, WIF1, Dkk3, and Hdpr1 was down-regulated due to abnormal promoter methylation in ALL cell lines and samples from patients with ALL. Methylation of Wnt inhibitors was associated with activation of the Wnt-signaling pathway as demonstrated by the up-regulation of the Wnt target genes WNT16, FZ3, TCF1, LEF1, and cyclin D1 in cell lines and samples and the nuclear localization of beta-catenin in cell lines. Treatment of ALL cells with the Wnt inhibitor quercetin or with the demethylating agent 5-aza-2'-deoxycytidine induced an inactivation of the Wnt pathway and induced apoptosis of ALL cells. Finally, in a group of 261 patients with newly diagnosed ALL, abnormal methylation of Wnt inhibitors was associated with decreased 10-year disease-free survival (25% versus 66% respectively, P < .001) and overall survival (28% versus 61% respectively, P = .001). Our results indicate a role of abnormal Wnt signaling in ALL and establish a group of patients with a significantly worse prognosis (methylated group).
Wnt/β-连环蛋白信号通路的激活是多种实体瘤的一个标志。我们分析了急性淋巴细胞白血病（ALL）中Wnt/β-连环蛋白通路的调控及其在该疾病发病机制中的作用。我们发现，由于ALL细胞系和ALL患者样本中启动子异常甲基化，Wnt抑制剂sFRP1、sFRP2、sFRP4、sFRP5、WIF1、Dkk3和Hdpr1的表达下调。Wnt抑制剂的甲基化与Wnt信号通路的激活相关，这在细胞系和样本中Wnt靶基因WNT16、FZ3、TCF1、LEF1和细胞周期蛋白D1的上调以及细胞系中β-连环蛋白的核定位中得到证实。用Wnt抑制剂槲皮素或去甲基化剂5-氮杂-2'-脱氧胞苷处理ALL细胞可诱导Wnt通路失活并诱导ALL细胞凋亡。最后，在一组261例新诊断的ALL患者中，Wnt抑制剂的异常甲基化与10年无病生存率降低（分别为25%对66%，P <.001）和总生存率降低（分别为28%对61%，P =.001）相关。我们的结果表明异常Wnt信号在ALL中起作用，并确定了一组预后明显较差的患者（甲基化组）。
