Institute of Immunology, University Hospital, 89081 Ulm, Germany; Department of Dermatology, University Hospital, 89081 Ulm, Germany.
Institute of Immunology, University Hospital, 89081 Ulm, Germany.
Cell Stem Cell. 2016 Dec 1;19(6):752-767. doi: 10.1016/j.stem.2016.08.007. Epub 2016 Sep 15.
Mouse mutants with an impaired DNA damage response frequently exhibit a set of remarkably similar defects in the HSPC compartment that are of largely unknown molecular basis. Using Mixed-Lineage-Leukemia-5 (Mll5)-deficient mice as prototypical examples, we have identified a mechanistic pathway linking DNA damage and HSPC malfunction. We show that Mll5 deficiency results in accumulation of DNA damage and reactive oxygen species (ROS) in HSPCs. Reduction of ROS efficiently reverses hematopoietic defects, establishing ROS as a major cause of impaired HSPC function. The Ink4a/Arf locus also contributes to HSPC phenotypes, at least in part via promotion of ROS. Strikingly, toxic ROS levels in Mll5 mice are critically dependent on type 1 interferon (IFN-1) signaling, which triggers mitochondrial accumulation of full-length Bid. Genetic inactivation of Bid diminishes ROS levels and reverses HSPC defects in Mll5 mice. Overall, therefore, our findings highlight an unexpected IFN-1 > Bid > ROS pathway underlying DNA damage-associated HSPC malfunction.
在 DNA 损伤反应受损的小鼠突变体中，造血干/祖细胞（HSPC）中经常出现一组非常相似的缺陷，其分子基础在很大程度上是未知的。我们使用混合谱系白血病-5（Mll5）缺陷型小鼠作为典型例子，确定了一个将 DNA 损伤和 HSPC 功能障碍联系起来的机制途径。我们发现，Mll5 缺陷导致 HSPC 中 DNA 损伤和活性氧（ROS）的积累。ROS 的减少可有效地逆转造血缺陷，表明 ROS 是 HSPC 功能障碍的主要原因。Ink4a/Arf 基因座也至少部分地通过促进 ROS 对 HSPC 表型有贡献。引人注目的是，Mll5 小鼠中有毒的 ROS 水平严重依赖于 I 型干扰素（IFN-1）信号，该信号触发全长 Bid 的线粒体积累。Bid 的基因失活可降低 ROS 水平并逆转 Mll5 小鼠中的 HSPC 缺陷。因此，总的来说，我们的研究结果强调了一种意想不到的 IFN-1 > Bid > ROS 途径，它是与 DNA 损伤相关的 HSPC 功能障碍的基础。
