Induction of human fetal hemoglobin via the NRF2 antioxidant response signaling pathway
Induction of human fetal hemoglobin via the NRF2 antioxidant response signaling pathway
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DOI：
10.1182/blood-2010-10-314096
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发表时间：
2011-06-02
期刊：
影响因子：
20.3
通讯作者：
Lowrey, Christopher H.
中科院分区：
文献类型：
--
作者：
Macari, Elizabeth R.;Lowrey, Christopher H.
尽管造血干细胞移植和基因治疗有可能治愈β地中海贫血和镰状细胞病，但目前大多数患有这些疾病的人还无法使用它们。在短期内，药物诱导胎儿血红蛋白 (HbF) 可能为安全、有效和广泛使用的治疗提供最佳可能性。为了确定 HbF 诱导靶向药物开发的新途径，我们评估了核因子红细胞 2 相关因子 2 (NRF2) 抗氧化反应元件信号传导途径。我们发现该途径的 3 种众所周知的激活剂在 K562 细胞中以无毒剂量增加了 γ-珠蛋白 mRNA。叔丁基氢醌 (tBHQ) 是这些化合物中最活跃的，它增加了 NRF2 的细胞水平和核转位以及 NRF2 与 γ-珠蛋白启动子的结合。 NRF2 的 siRNA 敲低抑制了 tBHQ 诱导的伽马珠蛋白。在人原代红系细胞中进行测试时，tBHQ 诱导 NRF2 与 γ 珠蛋白启动子结合，增加 γ 珠蛋白 mRNA 和 HbF，并抑制 β 珠蛋白 mRNA 和 HbA，导致 HbF 百分比增加 3 倍以上。这些结果表明，激活 NRF2/抗氧化反应元件信号通路的药物有可能诱导 β-血红蛋白病患者的 HbF 达到治疗水平。 （血。2011；117（22）：5987-5997）
Although hematopoietic stem cell transplantation and gene therapy have the potential to cure beta-thalassemia and sickle cell disease, they are not currently available to most people with these diseases. In the near term, pharmacologic induction of fetal hemoglobin (HbF) may offer the best possibility for safe, effective, and widely available therapy. In an effort to define new pathways for targeted drug development for HbF induction, we evaluated the nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant response element signaling pathway. We found that 3 well-known activators of this pathway increased gamma-globin mRNA at nontoxic doses in K562 cells. Tert-butylhydroquinone (tBHQ), the most active of these compounds, increased cellular levels and nuclear translocation of NRF2 and binding of NRF2 to the gamma-globin promoter. siRNA knockdown of NRF2 inhibited gamma-globin induction by tBHQ. When tested in human primary erythroid cells, tBHQ induced NRF2 binding to the gamma-globin promoter, increased gamma-globin mRNA and HbF, and suppressed beta-globin mRNA and HbA, resulting in a >3-fold increase in the percentage of HbF. These results suggest that drugs that activate the NRF2/antioxidant response element signaling pathway have the potential to induce therapeutic levels of HbF in people with beta-hemoglobinopathies. (Blood. 2011; 117(22): 5987-5997)