# Cross-talk mechanisms between RUNX1 and inflammatory signals impacting functions of stem and progenitors in Familial Platelet Disorder.

> **NIH NIH F31** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $10,986

## Abstract

PROJECT SUMMARY
Germline cancer predispositions are well established for solid tumors. Once thought to be a rare event,
predispositions to myeloid malignancies are now included in the latest leukemia classification scheme from the
World Health Organization. Thus, more patients are expected to be recognized as carriers which can create a
constant fear of developing leukemia in their families. Given the best treatment is prevention, understanding the
important factors in transitioning from pre-malignant to overt disease stage is fundamental in establishing
guidelines for monitoring and treatment of such patients. Of many leukemia predisposition syndromes, we focus
on familial platelet disorders (FPD) caused by monoallelic RUNX1 germline mutations in. RUNX1-mutations in
FPD lead to bleeding disorders, lower counts and dysfunction of platelets. FPD is one of the most common forms
of inherited myeloid malignancies, and patients have ~40% life-long chance of developing leukemia at median
age of 33 years. The transition to overt leukemia is accompanied by acquisition of secondary mutations, though
the complete mechanism of disease transformationis unknown. Intriguingly, FPD patients manifest with different
allergies such as skin eczema, indicating the possible role of increased inflammation in driving leukemia
development. Therefore, we propose that inflammatory stress facilitates leukemia initiation and progression in
FPD. To test this, we performed series of experiments using primary FPD bone marrow cells. We observed that
FPD hematopoietic stem and progenitors (HSPCs) show myeloid biased differentiation and increased colony
formation ability, while fall behind in megakaryocyte differentiation. Single cell transcriptome analysis of healthy
and FPD bone marrow cells confirmed the skewed differentiation of progenitors and identified enrichment of
inflammatory response pathways in FPD compared to healthy stem cells. Consistently, we found upregulation
of inflammatory cytokines in the bone marrow niche, including from mesenchymal stromal cells. Therefore, I
hypothesize that a cross-talk between RUNX1-mutations mediated changes in HSPCs and inflammatory
microenvironment promotes myeloid growth and differentiation defects in FPD stem and progenitor
cells. To address this hypothesis, in Aim 1, I will evaluate the impact of inflammatory stress on growth and
differentiation of FPD and healthy HSPCs. I will use the genetic or pharmacological inhibition approaches to
dissect the mechanism by which inflammatory stress impacts the functions of FPD HSPCs. Then, I will identify
whether these effects are directly regulated by RUNX1 using CUT&Tag experiments. In Aim 2, I will determine
the effect of RUNX1-mutated bone marrow stromal cells on the function of FPD and healthy HSPCs using newly
established 3D co-culture methods. Then, I will use a unique mouse model with germline Runx1-hetrozygous
mutation to determine the role of bone marrow niche on stem cell growth and...

## Key facts

- **NIH application ID:** 10830281
- **Project number:** 5F31HL162542-03
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Mona MohammadHosseini
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $10,986
- **Award type:** 5
- **Project period:** 2022-04-25 → 2024-06-23

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10830281

## Citation

> US National Institutes of Health, RePORTER application 10830281, Cross-talk mechanisms between RUNX1 and inflammatory signals impacting functions of stem and progenitors in Familial Platelet Disorder. (5F31HL162542-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10830281. Licensed CC0.

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