Specific molecular signatures predict decitabine response in chronic myelomonocytic leukemia
Specific molecular signatures predict decitabine response in chronic myelomonocytic leukemia
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DOI：
10.1172/jci78752
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发表时间：
2015-05-01
影响因子：
15.9
通讯作者：
Figueroa, Maria E.
中科院分区：
文献类型：
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作者：
Meldi, Kristen;Qin, Tingting;Figueroa, Maria E.
骨髓增生异常综合征和慢性粒单核细胞白血病(CMML)的特征是编码表观遗传修饰因子的基因突变和异常的DNA甲基化。DNA甲基转移酶抑制剂(DMTI)被用于治疗这些疾病，但反应高度可变，几乎没有方法预测哪些患者将受益。在这里，我们检查了40名对地西他滨(DAC)敏感或耐药的CMML患者的突变、DNA甲基化和基因表达的基线差异，以开发一种预测诊断反应的分子手段。虽然体细胞突变不能区分应答和无应答，但我们使用下一代测序技术在基线上识别了167个区分应答和无应答的DNA差异甲基化区域(DMR)。这些DMR主要定位于非启动子区域，并与远端调控增强子重叠。利用甲基化图谱，我们开发了一种表观遗传学分类器，可以准确地预测诊断时的DAC反应。转录分析显示，应答者和无应答者在诊断时基因表达存在差异。在应答者中，上调的基因包括那些与细胞周期相关的基因，可能有助于有效地掺入DAC。CXCL4和CXCL7在无反应者中过度表达，阻断了分离的正常CD34(+)和原代CMML细胞的DAC效应，表明它们的上调参与了原发DAC耐药。
Myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML) are characterized by mutations in genes encoding epigenetic modifiers and aberrant DNA methylation. DNA methyltransferase inhibitors (DMTis) are used to treat these disorders, but response is highly variable, with few means to predict which patients will benefit. Here, we examined baseline differences in mutations, DNA methylation, and gene expression in 40 CMML patients who were responsive or resistant to decitabine (DAC) in order to develop a molecular means of predicting response at diagnosis. While somatic mutations did not differentiate responders from nonresponders, we identified 167 differentially methylated regions (DMRs) of DNA at baseline that distinguished responders from nonresponders using next-generation sequencing. These DMRs were primarily localized to nonpromoter regions and overlapped with distal regulatory enhancers. Using the methylation profiles, we developed an epigenetic classifier that accurately predicted DAC response at the time of diagnosis. Transcriptional analysis revealed differences in gene expression at diagnosis between responders and nonresponders. In responders, the upregulated genes included those that are associated with the cell cycle, potentially contributing to effective DAC incorporation. Treatment with CXCL4 and CXCL7, which were overexpressed in nonresponders, blocked DAC effects in isolated normal CD34(+) and primary CMML cells, suggesting that their upregulation contributes to primary DAC resistance.