# Determining how RUNX1 regulates the inflammatory response in neutrophils

> **NIH NIH F30** · UNIVERSITY OF PENNSYLVANIA · 2022 · $34,192

## Abstract

PROJECT SUMMARY:
Loss of function mutations in the transcription factor RUNX1 often occur in acute myeloid leukemia (AML) and
myelodysplastic syndrome (MDS). Patients carrying inherited RUNX1 mutations are predisposed to developing
clonal hematopoiesis, myelodysplastic syndrome, and leukemia. Interestingly, patients with inherited RUNX1
mutations are predisposed to developing inflammatory disorders such as asthma and eczema. RUNX1 mutations
and their contributions to oncogenesis are well described. However, the broader effects of RUNX1 mutations on
inflammatory responses are poorly understood. Our lab recently demonstrated that RUNX1 has a significant role
in regulating inflammatory responses in mouse neutrophils. Pan- hematopoietic RUNX1 loss activated an
inflammatory transcriptional program that primed neutrophils to hyperactivate in response to toll-like receptor
4 (TLR4) stimulation. Since neutrophils are an important component of the bone marrow niche, we hypothesize
that increased inflammatory cytokine and chemokine production by neutrophils may contribute to the elevated
risk of clonal hematopoiesis and leukemia in patients with RUNX1 mutations. The goal of this proposal is to
understand the mechanisms by which RUNX1 regulates inflammation in neutrophils. I hypothesize that
alterations in the TLR4 signaling pathway are established in a neutrophil precursor by an alteration in the
progenitor epigenome that is then propagated to differentiated neutrophils, causing them to hyper-respond to
TLR4 ligands. The first goal of my proposal is to test this hypothesis. The second goal is to determine whether
RUNX1 directly regulates the expression of TLR4 pathway genes in neutrophil precursors, or if RUNX1 loss in
other hematopoietic cells contributes to the inflammatory neutrophil response.

## Key facts

- **NIH application ID:** 10386006
- **Project number:** 1F30DK128926-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Alexandra Zezulin
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $34,192
- **Award type:** 1
- **Project period:** 2022-07-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10386006

## Citation

> US National Institutes of Health, RePORTER application 10386006, Determining how RUNX1 regulates the inflammatory response in neutrophils (1F30DK128926-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10386006. Licensed CC0.

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