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

Abstract

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.

Heterozygous variants in KMT2E cause a spectrum of neurodevelopmental disorders and epilepsy

“…Several Kmt2e (Mll5) deficiency mouse models have been created and characterized 15,[19][20][21][22] . These mice present with growth restriction and increased mortality, as well as impaired hematopoiesis.…”

“…A neurological phenotype in these mice has not been reported. Both homozygous and heterozygous loss of Kmt2e in mice results in DNA damage and elevated levels of reactive oxygen species (ROS) 22 . The cellular effects were effectively reversed by supplementation with the glutathione precursor, Nacetylcysteine (NAC) 22 .…”

Type-I-interferons in infection and cancer: Unanticipated dynamics with therapeutic implications

“…72 This phenomenon was mainly due to Type-I-IFN-induced accumulation of reactive oxygen species (ROS). 73 Additional indirect proofs of the tumor growth promoting role of Type-I-IFNs come from recent studies showing that, in cancer cells, Type-I-IFNs upregulated the ISG programmed death-ligand (PD-L)1 74 (panel 8, Fig. 2).…”

The IFN-1 > BID > ROS pathway: Linking DNA damage with HSPC malfunction

“…Several observations, including upregulation of Sca-1, phosphorylation of STAT-1 and transcriptional induction of select IFN-1 target genes, indicated active type I interferon (IFN-1) signaling in HSPCs lacking MLL5. 1 Remarkably, genetic abrogation of IFN-1 signaling in Mll5 ¡/¡ x Ifnar1 ¡/¡ mice lacking an essential subunit of the IFN-1 receptor reduced ROS to near wild-type levels and markedly restored HSPC function despite absence of MLL5. This striking result identifies IFN-1 signaling as hitherto unknown link between DNA damage and toxic ROS accumulation.…”

“…1 Indeed, appropriate assays revealed accrued DNA damage in HSPCs lacking MLL5. Moreover, MLL5-deficient HSPCs had drastically increased levels of ROS, and in vivo anti-oxidant treatment efficiently restored HSPC function, as reported previously for mice lacking Ataxia Telangiectasia Mutated (ATM) kinase, a key player in DDR.…”