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

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 in HSPCs. Reduction of efficiently reverses hematopoietic defects, establishing duanyu1670 as a major cause of impaired HSPC function. The Ink4a/Arf locus also contributes to HSPC phenotypes, at least in part via promotion of Strikingly, toxic 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 duanyu1670 levels and reverses HSPC defects in Mll5^-/- mice. Overall, therefore, our findings highlight an unexpected IFN-1 > Bid > duanyu1670 pathway underlying DNA damage-associated HSPC malfunction.

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