DNA Damage-Induced HSPC Malfunction Depends on ROS Accumulation Downstream of IFN-1 Signaling and Bid Mobilization

• Published in: Cell stem cell 2016-12, Vol.19 (6), p.752-767
• Main Authors: Tasdogan, Alpaslan, Kumar, Suresh, Allies, Gabriele, Bausinger, Julia, Beckel, Franziska, Hofemeister, Helmut, Mulaw, Medhanie, Madan, Vikas, Scharffetter-Kochanek, Karin, Feuring-Buske, Michaela, Doehner, Konstanze, Speit, Günter, Stewart, A. Francis, Fehling, Hans Joerg
• Format: Article
• Language: English
• Subjects: Acetylcysteine - administration & dosage; Acetylcysteine - pharmacology; Administration, Oral; Animals; Animals, Newborn; BH3 Interacting Domain Death Agonist Protein - metabolism; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; DNA Damage; Genetic Loci; Hematopoiesis - drug effects; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Histone-Lysine N-Methyltransferase; Interferon Type I - metabolism; Intracellular Space - metabolism; Mice; Poly I-C - pharmacology; Protein Transport - drug effects; Reactive Oxygen Species - metabolism; Receptors, Interferon - metabolism; Signal Transduction - drug effects; Survival Analysis
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2016.08.007

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. [Display omitted] •HSPCs in Mll5-deficient mice accumulate DNA damage and ROS•NAC administration to counteract ROS activity markedly restores HSPC function•The Ink4a/Arf locus contributes to ROS production and hematopoietic defects•IFN-1-dependent Bid mobilization is key for toxic ROS accumulation Tasdogan et al. identify toxic levels of reactive oxygen species (ROS) as major culprit underlying HSPC malfunction in a mouse mutant with defective DNA repair. They further demonstrate that high ROS levels in HSPCs are dependent on DNA damage-associated IFN-1 signaling and the Bcl-2 homolog Bid.