National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
National Cancer Institute, National Institutes of Health, Frederick, MD.
Exp Hematol. 2019 May;73:1-6.e6. doi: 10.1016/j.exphem.2019.03.002. Epub 2019 Apr 13.
A causal link between hematopoietic stem/progenitor cell (HSPC) dysfunction and DNA damage accrual has been proposed. Clinically relevant strategies to maintain genome integrity in these cells are needed. Here we report that eltrombopag, a small molecule agonist of the thrombopoietin (TPO) receptor used in the clinic, promotes DNA double-strand break (DSB) repair in human HSPCs. We found that eltrombopag specifically activates the classic nonhomologous end-joining (C-NHEJ) DNA repair mechanism, a pathway known to support genome integrity. Eltrombopag-mediated DNA repair results in enhanced genome stability, survival, and function of primary human HSPCs, as demonstrated in karyotyping analyses, colony-forming unit assays and after transplantation in immunodeficient NSG mice. Eltrombopag may offer a new therapeutic modality to protect human HSPCs against genome insults.
造血干/祖细胞（HSPC）功能障碍与 DNA 损伤积累之间存在因果关系。临床上需要维持这些细胞中基因组完整性的相关策略。在这里，我们报告说，临床上使用的血小板生成素（TPO）受体小分子激动剂艾曲波帕可促进人 HSPC 中的 DNA 双链断裂（DSB）修复。我们发现，艾曲波帕特异性激活经典的非同源末端连接（C-NHEJ）DNA 修复机制，这是一种已知支持基因组完整性的途径。艾曲波帕介导的 DNA 修复导致人类 HSPC 中染色体核型分析、集落形成单位测定以及移植到免疫缺陷性 NSG 小鼠后的基因组稳定性、存活和功能增强。艾曲波帕可能为保护人类 HSPC 免受基因组损伤提供一种新的治疗模式。
