Liu Te-Hui, Raval Aparna, Chen Shih-Shih, Matkovic Jennifer J, Byrd John C, Plass Christoph
Department of Molecular Virology, Immunology, and Medical Genetics, Division of Human Cancer Genetics, The Ohio State University, 420 West 12th Avenue, Columbus, OH 43210, USA.
Cancer Res. 2006 Jan 15;66(2):653-8. doi: 10.1158/0008-5472.CAN-05-3712.
B-cell chronic lymphocytic leukemia (CLL) is characterized by a clonal accumulation of mature neoplastic B cells indicating disruption of apoptosis. Restriction Landmark Genome Scanning was done to identify novel target genes silenced by CpG island methylation in CLL. Secreted frizzled-related protein 4 (SFRP4), a negative regulator of the Wnt signaling pathway, was found to be frequently methylated in CLL samples. Wnt signaling has been shown to control normal apoptotic behavior and is required for normal B-cell development whereas aberrant activation of this pathway has been observed in CLL. We show aberrant DNA methylation and silencing of SFRP4, as well as of additional SFRP family members, in primary CLL samples. Induction of their expression in a dose-dependent manner following treatment with a demethylating agent, 5-aza-2'-deoxycytidine, was shown. Of the five SFRP family members studied in detail, SFRP1 was hypermethylated and down-regulated in all CLL patient samples studied, suggesting that this epigenetic event is a critical step during leukemogenesis. Our results suggest that silencing of SFRPs by CpG island methylation is one possible mechanism contributing to aberrant activation of Wnt signaling pathway in CLL.
B细胞慢性淋巴细胞白血病（CLL）的特征是成熟肿瘤性B细胞的克隆性积聚，这表明细胞凋亡受到破坏。采用限制性内切酶指纹图谱基因组扫描技术来识别CLL中因CpG岛甲基化而沉默的新靶基因。分泌型卷曲相关蛋白4（SFRP4）是Wnt信号通路的负调节因子，在CLL样本中发现其经常发生甲基化。Wnt信号已被证明可控制正常的凋亡行为，并且是正常B细胞发育所必需的，而在CLL中已观察到该信号通路的异常激活。我们发现原发性CLL样本中SFRP4以及其他SFRP家族成员存在异常的DNA甲基化和沉默。用去甲基化剂5-氮杂-2'-脱氧胞苷处理后，它们的表达呈剂量依赖性诱导。在详细研究的五个SFRP家族成员中，SFRP1在所有研究的CLL患者样本中均发生高甲基化并下调，这表明这种表观遗传事件是白血病发生过程中的关键步骤。我们的结果表明，CpG岛甲基化导致SFRP家族基因沉默是CLL中Wnt信号通路异常激活的一种可能机制。
