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UNC0638 induces high levels of fetal hemoglobin expression in β-thalassemia/HbE erythroid progenitor cells.

UNC0638在 β-地中海贫血/HbE红系祖细胞中诱导高水平的胎儿血红蛋白表达。

  • 影响因子:1.94
  • DOI:10.1007/s00277-020-04136-w
  • 作者列表:"Nualkaew T","Khamphikham P","Pongpaksupasin P","Kaewsakulthong W","Songdej D","Paiboonsukwong K","Sripichai O","Engel JD","Hongeng S","Fucharoen S","Jearawiriyapaisarn N
  • 发表时间:2020-09-01
Abstract

:Increased expression of fetal hemoglobin (HbF) improves the clinical severity of β-thalassemia patients. EHMT1/2 histone methyltransferases are epigenetic modifying enzymes that are responsible for catalyzing addition of the repressive histone mark H3K9me2 at silenced genes, including the γ-globin genes. UNC0638, a chemical inhibitor of EHMT1/2, has been shown to induce HbF expression in human erythroid progenitor cell cultures. Here, we report the HbF-inducing activity of UNC0638 in erythroid progenitor cells from β-thalassemia/HbE patients. UNC0638 treatment led to significant increases in γ-globin mRNA, HbF expression, and HbF-containing cells in the absence of significant cytotoxicity. Moreover, UNC0638 showed additive effects on HbF induction in combination with the immunomodulatory drug pomalidomide and the DNMT1 inhibitor decitabine. These studies provide a scientific proof of concept that a small molecule targeting EHMT1/2 epigenetic enzymes, used alone or in combination with pomalidomide or decitabine, is a potential therapeutic approach for HbF induction. Further development of structural analogs of UNC0638 with similar biological effects but improved pharmacokinetic properties may lead to promising therapies and possible clinical application for the treatment of β-thalassemia.

摘要

: 胎儿血红蛋白 (HbF) 表达增加改善 β-地中海贫血患者的临床严重程度。EHMT1/2组蛋白甲基转移酶是表观遗传修饰酶,负责催化抑制性组蛋白标记H3K9me2在沉默基因 (包括 γ-珠蛋白基因) 上的添加。UNC0638,一种EHMT1/2的化学抑制剂,已显示在人红系祖细胞培养物中诱导HbF表达。在此,我们报道了UNC0638在 β-地中海贫血/HbE患者红系祖细胞中的HbF诱导活性。UNC0638处理导致 γ-珠蛋白mRNA、HbF表达和含HbF的细胞在没有显著细胞毒性的情况下显著增加。此外,UNC0638显示与免疫调节药物泊马度胺和DNMT1抑制剂地西他滨组合对HbF诱导的累加效应。这些研究提供了一个概念的科学证明,即单独或与泊马度胺或地西他滨组合使用的靶向EHMT1/2表观遗传酶的小分子是HbF诱导的潜在治疗方法。进一步开发具有相似生物学效应但改善药代动力学性质的UNC0638结构类似物可能导致治疗 β-地中海贫血的有希望的疗法和可能的临床应用。

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影响因子:1.74
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翻译标题与摘要 下载文献
血红蛋白病方向

由于血红蛋白分子结构异常(异常血红蛋白病),或珠蛋白肽链合成速率异常(珠蛋白生成障碍性贫血,又称海洋性贫血)所引起的一组遗传性血液病。

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