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ZBP1 activation triggers hematopoietic stem and progenitor cell death resulting in bone marrow failure in mice.
Roderick-Richardson, Justine E; Lim, Sung-Eun; Suzuki, Sakiko; Ahmad, Mohd Hafiz; Selway, Jonathan; Suleiman, Reem; Karna, Keshab; Lehman, Jesse; O'Donnell, Joanne; Castilla, Lucio H; Maelfait, Jonathan; Rehwinkel, Jan; Kelliher, Michelle A.
Affiliation
  • Roderick-Richardson JE; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605.
  • Lim SE; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605.
  • Suzuki S; Department of Medicine, Division of Hematology-Oncology, University of Massachusetts Chan Medical School, Worcester, MA 01605.
  • Ahmad MH; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605.
  • Selway J; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605.
  • Suleiman R; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605.
  • Karna K; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605.
  • Lehman J; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605.
  • O'Donnell J; School of Biological Sciences, Monash University, Clayton, VIC 3800, Australia.
  • Castilla LH; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605.
  • Maelfait J; Vlaams Instituut voor Biotechnologie-UGent Center for Inflammation Research, Ghent 9052, Belgium.
  • Rehwinkel J; Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, United Kingdom.
  • Kelliher MA; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605.
Proc Natl Acad Sci U S A ; 121(4): e2309628121, 2024 Jan 23.
Article in En | MEDLINE | ID: mdl-38227660
ABSTRACT
Human bone marrow failure (BMF) syndromes result from the loss of hematopoietic stem and progenitor cells (HSPC), and this loss has been attributed to cell death; however, the cell death triggers, and mechanisms remain unknown. During BMF, tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ) increase. These ligands are known to induce necroptosis, an inflammatory form of cell death mediated by RIPK1, RIPK3, and MLKL. We previously discovered that mice with a hematopoietic RIPK1 deficiency (Ripk1HEM KO) exhibit inflammation, HSPC loss, and BMF, which is partially ameliorated by a RIPK3 deficiency; however, whether RIPK3 exerts its effects through its function in mediating necroptosis or other forms of cell death remains unclear. Here, we demonstrate that similar to a RIPK3 deficiency, an MLKL deficiency significantly extends survival and like Ripk3 deficiency partially restores hematopoiesis in Ripk1HEM KO mice revealing that both necroptosis and apoptosis contribute to BMF in these mice. Using mouse models, we show that the nucleic acid sensor Z-DNA binding protein 1 (ZBP1) is up-regulated in mouse RIPK1-deficient bone marrow cells and that ZBP1's function in endogenous nucleic acid sensing is necessary for HSPC death and contributes to BMF. We also provide evidence that IFNγ mediates HSPC death in Ripk1HEM KO mice, as ablation of IFNγ but not TNFα receptor signaling significantly extends survival of these mice. Together, these data suggest that RIPK1 maintains hematopoietic homeostasis by preventing ZBP1 activation and induction of HSPC death.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pancytopenia / Nucleic Acids Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Proc Natl Acad Sci U S A Year: 2024 Type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pancytopenia / Nucleic Acids Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Proc Natl Acad Sci U S A Year: 2024 Type: Article