Stresemann Carlo, Bokelmann Imke, Mahlknecht Ulrich, Lyko Frank
Division of Epigenetics, German Cancer Research Center, Germany.
Mol Cancer Ther. 2008 Sep;7(9):2998-3005. doi: 10.1158/1535-7163.MCT-08-0411.
Aberrant DNA methylation patterns play an important role in the pathogenesis of hematologic malignancies. The DNA methyltransferase inhibitors azacytidine and decitabine have shown significant clinical benefits in the treatment of myelodysplastic syndrome (MDS), but their precise mode of action remains to be established. Both drugs have been shown the ability to deplete DNA methyltransferase enzymes and to induce DNA demethylation and epigenetic reprogramming in vitro. However, drug-induced methylation changes have remained poorly characterized in patients and therapy-related models. We have now analyzed azacytidine-induced demethylation responses in myeloid leukemia cell lines. These cells showed remarkable differences in the drug-induced depletion of DNA methyltransferases that coincided with their demethylation responses. In agreement with these data, DNA methylation analysis of blood and bone marrow samples from MDS patients undergoing azacytidine therapy also revealed substantial differences in the epigenetic responses of individual patients. Significant, transient demethylation could be observed in 3 of 6 patients and affected many hypermethylated loci in a complex pattern. Our results provide important proof-of-mechanism data for the demethylating activity of azacytidine in MDS patients and provide detailed insight into drug-induced demethylation responses.
异常的DNA甲基化模式在血液系统恶性肿瘤的发病机制中起重要作用。DNA甲基转移酶抑制剂阿扎胞苷和地西他滨在骨髓增生异常综合征（MDS）的治疗中已显示出显著的临床益处，但其确切作用方式仍有待确定。这两种药物均已显示出在体外耗尽DNA甲基转移酶以及诱导DNA去甲基化和表观遗传重编程的能力。然而，在患者和治疗相关模型中，药物诱导的甲基化变化仍未得到充分表征。我们现在分析了阿扎胞苷在髓系白血病细胞系中诱导的去甲基化反应。这些细胞在药物诱导的DNA甲基转移酶耗竭方面表现出显著差异，这与其去甲基化反应一致。与这些数据一致，对接受阿扎胞苷治疗的MDS患者的血液和骨髓样本进行的DNA甲基化分析也揭示了个体患者表观遗传反应的显著差异。在6名患者中的3名患者中可观察到显著的、短暂的去甲基化，并且以复杂的模式影响了许多高甲基化位点。我们的结果为阿扎胞苷在MDS患者中的去甲基化活性提供了重要的机制验证数据，并提供了对药物诱导的去甲基化反应的详细见解。
