# Molecular mechanism underlying clonal expansion of hematopoietic stem cells

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $678,278

## Abstract

PROJECT SUMMARY
Clonal hematopoiesis of indeterminate potential (CHIP) increases with age and occurs when a single mutant
hematopoietic stem cell (HSC) contributes to a significant clonal proportion of mature blood lineages. CHIP is
associated with increased risks of developing hematological malignancies. TP53 mutations rank in the top 5
among mutations identified in CHIP and clinical studies showed that expansion of TP53 mutated HSCs with
age predisposes individuals with CHIP to myeloid neoplasms such as myelodysplastic syndromes (MDS).
During the previous funding period, we found that mutant p53 utilizes a cell intrinsic mechanism to drive clonal
hematopoiesis through enhancing EZH2 activity and increasing H3K27me3 in HSCs. However, there is a
significant gap in knowledge regarding the mechanisms by which extrinsic factors drive TP53 mutant clonal
hematopoiesis. In the competitive renewal, we will focus on determining the impact of inflammatory stress on
TP53 mutant clonal hematopoiesis and developing novel strategies for preventing the progression of clonal
hematopoiesis to MDS. Infection activates inflammatory response and induces chronic inflammation. We
discovered that bacterial infection confers a competitive advantage to p53 mutant hematopoietic stem and
progenitor cells (HSPCs) via activating the NLRP1 inflammasome and increasing the secretion of
proinflammatory cytokines. Furthermore, we found that some p53 mutant mice developed MDS with age and
that there are increased levels of IL-1β and IL-6 in the BM of aged p53 mutant mice. We hypothesize that
mutant p53 enhances inflammatory stress via activating the NLRP1 inflammasome and increasing the secretion
of proinflammatory cytokines, thereby generating a chronic inflammatory microenvironment that inhibits wild
type (WT) hematopoietic stem and progenitor cell (HSPC) fitness in a paracrine fashion. We further speculate
that reducing chronic inflammation will prevent or delay the progression of TP53 mutant clonal hematopoiesis
to myelodysplastic syndromes (MDS). To test the hypothesis, we will determine the mechanisms by which
inflammatory stress drives TP53 mutant clonal hematopoiesis. We will develop novel strategies that block
TP53 mutant clonal hematopoiesis from progression to MDS. Delineating the impact of inflammatory stress on
p53 mutant HSPC expansion will fill a significant knowledge gap regarding the mechanisms by which extrinsic
factors drive TP53 mutant clonal hematopoiesis and promote the development of MDS.

## Key facts

- **NIH application ID:** 10877535
- **Project number:** 2R01HL150624-05
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Yan Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $678,278
- **Award type:** 2
- **Project period:** 2019-07-15 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877535

## Citation

> US National Institutes of Health, RePORTER application 10877535, Molecular mechanism underlying clonal expansion of hematopoietic stem cells (2R01HL150624-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10877535. Licensed CC0.

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