Epigenetic and molecular profiles of erythroid cells after hydroxyurea treatment in sickle cell anemia
Epigenetic and molecular profiles of erythroid cells after hydroxyurea treatment in sickle cell anemia
复制标题
DOI：
10.1182/blood-2011-07-368746
复制
发表时间：
2011-11-17
期刊：
影响因子：
20.3
通讯作者：
Ware, Russell E.
中科院分区：
文献类型：
--
作者：
Walker, Aisha L.;Steward, Shirley;Ware, Russell E.
已证明，羟基脲可有效治疗镰状细胞性贫血（SCA），主要通过诱导胎儿血红蛋白（HbF）。然而，尽管已经提出了直接的转录作用和改变的细胞周期动力学，但羟基脲诱导HbF的确切机制仍不完全确定。在这项研究中，我们通过检测SCA患者的初级CD 71（+）红细胞内（G）γ-珠蛋白启动子内的甲基化模式和miRNA表达，研究了羟基脲介导的HbF诱导的潜在表观遗传和替代分子机制，无论是在开始羟基脲治疗前的基线还是达到最大耐受剂量（MTD）后。使用横截面分析和配对样本分析，我们发现高度甲基化（G）γ-珠蛋白启动子与基线HbF水平呈负相关，但仅被羟基脲处理轻微改变。相反，几种特异性miRNA的表达在羟基脲治疗后显著增加，并且miR-26 b和miR-151- 3 p的表达均与MTD时的HbF水平相关。这些研究中发现的显著相关性表明，甲基化可能对基线HbF的调节很重要，但不是在羟基脲治疗后，而miRNA表达的变化可能与羟基脲介导的HbF诱导相关。本研究注册于ClinicalTrials.gov（NCT 00305175）。（血。2011;118（20）：5664-5670）
Hydroxyurea has been shown to be efficacious for the treatment of sickle cell anemia (SCA), primarily through the induction of fetal hemoglobin (HbF). However, the exact mechanisms by which hydroxyurea can induce HbF remain incompletely defined, although direct transcriptional effects and altered cell cycle kinetics have been proposed. In this study, we investigated potential epigenetic and alternative molecular mechanisms of hydroxyurea-mediated HbF induction by examining methylation patterns within the (G)gamma-globin promoter and miRNA expression within primary CD71(+) erythrocytes of patients with SCA, both at baseline before beginning hydroxyurea therapy and after reaching maximum tolerated dose (MTD). Using both cross-sectional analysis and paired-sample analysis, we found that the highly methylated (G)gamma-globin promoter was inversely correlated to baseline HbF levels, but only slightly altered by hydroxyurea treatment. Conversely, expression of several specific miRNAs was significantly increased after hydroxyurea treatment, and expression of miR-26b and miR-151-3p were both associated with HbF levels at MTD. The significant associations identified in these studies suggest that methylation may be important for regulation of baseline HbF, but not after hydroxyurea treatment, whereas changes in miRNA expression may be associated with hydroxyurea-mediated HbF induction. This study was registered at ClinicalTrials.gov (NCT00305175). (Blood. 2011;118(20):5664-5670)