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

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 bindsCd14and 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.

Dysregulated innate immune signaling cooperates with RUNX1 mutations to transform an MDS-like disease to AML

“…RUNX1 is crucial for epigenetically repressing two inflammatory signaling pathways: TLR4 and type I IFN signaling. 23 , 24 Loss of RUNX1 in granulocyte-monocyte progenitors (GMPs) increases neutrophils’ inflammatory response to lipopolysaccharides (LPS), partly through elevated CD14 expression. 24 RUNX1 binds CD14 and other genes in the TLR4 and IFN pathways, leading to increased chromatin accessibility when RUNX1 is absent.…”

“… 23 , 24 Loss of RUNX1 in granulocyte-monocyte progenitors (GMPs) increases neutrophils’ inflammatory response to lipopolysaccharides (LPS), partly through elevated CD14 expression. 24 RUNX1 binds CD14 and other genes in the TLR4 and IFN pathways, leading to increased chromatin accessibility when RUNX1 is absent. Consistent with these observations, Runx1 R188Q mutation in mice lead to increased HSPCs, in part due to systemic inflammation.…”

“… 20 , 21 Furthermore, RUNX1 mutations are linked to altered innate immune and inflammatory signaling and often act as secondary hits in the progression from MDS to AML. 22 , 23 , 24 Therefore, our study aimed to investigate whether RUNX1 mutations could lead to the development of overt AML in preleukemic cells displaying cell-intrinsic innate immune activation.…”