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RUNX1 is required in granulocyte-monocyte progenitors to attenuate inflammatory cytokine production by neutrophils.

Authors
  • Zezulin, Alexandra U1
  • Yen, Daniel1
  • Ye, Darwin2
  • Howell, Elizabeth D1
  • Bresciani, Erica3
  • Diemer, Jamie3
  • Ren, Jian-Gang4
  • Ahmad, Mohd Hafiz5
  • Castilla, Lucio H5
  • Touw, Ivo P6
  • Minn, Andy J2
  • Tong, Wei4
  • Liu, P Paul3
  • Tan, Kai4, 7
  • Yu, Wenbao8, 7
  • Speck, Nancy A9
  • 1 Department of Cell and Developmental Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
  • 2 Department of Radiation Oncology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
  • 3 Oncogenesis and Development Section, Division of Intramural Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • 4 Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
  • 5 Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
  • 6 Department of Hematology, Erasmus Medical College, Rotterdam 3015CN, the Netherlands. , (Netherlands)
  • 7 Division of Oncology and Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
  • 8 Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; [email protected] [email protected].
  • 9 Department of Cell and Developmental Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; [email protected] [email protected].
Type
Published Article
Journal
Genes & development
Publication Date
Jul 01, 2023
Volume
37
Issue
13-14
Pages
605–620
Identifiers
DOI: 10.1101/gad.350418.123
PMID: 37536952
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The transcription factor RUNX1 is mutated in familial platelet disorder with associated myeloid malignancy (FPDMM) and in sporadic myelodysplastic syndrome and leukemia. RUNX1 was shown to regulate inflammation in multiple cell types. Here we show that RUNX1 is required in granulocyte-monocyte progenitors (GMPs) to epigenetically repress two inflammatory signaling pathways in neutrophils: Toll-like receptor 4 (TLR4) and type I interferon (IFN) signaling. RUNX1 loss in GMPs augments neutrophils' inflammatory response to the TLR4 ligand lipopolysaccharide through increased expression of the TLR4 coreceptor CD14. RUNX1 binds Cd14 and other genes encoding proteins in the TLR4 and type I IFN signaling pathways whose chromatin accessibility increases when RUNX1 is deleted. Transcription factor footprints for the effectors of type I IFN signaling-the signal transducer and activator of transcription (STAT1::STAT2) and interferon regulatory factors (IRFs)-were enriched in chromatin that gained accessibility in both GMPs and neutrophils when RUNX1 was lost. STAT1::STAT2 and IRF motifs were also enriched in the chromatin of retrotransposons that were derepressed in RUNX1-deficient GMPs and neutrophils. We conclude that a major direct effect of RUNX1 loss in GMPs is the derepression of type I IFN and TLR4 signaling, resulting in a state of fixed maladaptive innate immunity. © 2023 Zezulin et al.; Published by Cold Spring Harbor Laboratory Press.

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