RUNX1 IS REQUIRED IN GRANULOCYTE-MONOCYTE PROGENITORS TO ATTENUATE INFLAMMATORY CYTOKINE AND INTERFERON PRODUCTION BY NEUTROPHILS

The transcription factor RUNX1 is mutated in familial platelet disorder with associated myeloid malignancies (FPDMM) and in sporadic myelodysplastic syndrome and leukemia. RUNX1 regulates 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 the Cd14 gene and many genes encoding proteins in the type I IFN signaling pathway to restrain their chromatin accessibility. Transcription factor footprints for the effectors of type I IFN signaling, the signal transducer and activator of transcription (STAT1::STAT2), and interferon regulatory factors (IRF) were enriched in chromatin that gained accessibility in both GMPs and neutrophils when RUNX1 was lost. STAT2 and IRF motifs were also enriched in the chromatin of retrotransposons de-repressed in Runx1 deficient GMPs and neutrophils. We conclude that a direct effect of RUNX1 loss in GMPs is the de-repression of type I signaling, resulting in a state of fixed maladaptive innate immunity.