# Impact of IL-1 signaling on hematopoietic stem cell function and emergence of clonal hematopoiesis.

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $378,798

## Abstract

PROJECT SUMMARY
The long-term objective of this proposal is to identify mechanism(s) that promote clonal hematopoiesis of
indeterminate potential (CHIP). CHIP is a risk factor for cardiovascular disease, myeloid hematological
malignancy, and all-cause mortality. CHIP is thought to arise from mutant hematopoietic stem cells (HSC)
carrying oncogenic mutations that endow the cells with increased fitness, leading to expansion of the mutant
clone. Rare hematopoietic clones carrying CHIP-associated mutations are near-ubiquitous in healthy
individuals. However, CHIP is largely confined in older individuals or patients with a history of smoking, chemo-
or radiotherapy exposure. This suggests that physiological perturbation(s) unique to aging and genotoxin
exposure, such as chronic inflammation, are required to drive CHIP.
To better understand the mechanism underlying CHIP, we have conducted mouse studies that indicate chronic
IL-1 production in the BM is a common consequence of aging and exposure to radiation or chemotherapy. Our
preliminary data show that chronic IL-1 activates a cell growth arrest program associated with PU.1 induction in
long-term HSC (HSCLT). Strikingly, Tet2-deficient HSCLT fail to fully activate this growth arrest program during
IL-1 exposure. Along these lines, our data show that increased Tet2-deficient clonal expansion requires
chronic IL-1. These preliminary data suggest that clonal expansion of mutant HSC is an emergent feature
dependent on chronic inflammation.
The studies proposed here will identify and characterize the molecular and cellular mechanisms by which
chronic IL-1 promotes mutant HSC clonal expansion, using Tet2-deficiency as a model. Lines of investigation
will include molecular and cellular analyses of normal and Tet2-deficient HSC exposed to IL-1, and competitive
transplant assays to assess the functional impact of chronic IL-1 on normal and Tet2-deficient HSC fitness
side-by-side. Lastly, experiments will assess whether IL-1 blockade can restore normal HSC fitness and
reverse or limit clonal expansion. Altogether, our investigations could provide a basis for redefining CHIP as a
potentially reversible process of somatic evolution in which an inflammatory BM environment selects for mutant
HSC clones.

## Key facts

- **NIH application ID:** 9850247
- **Project number:** 5R01DK119394-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Eric M Pietras
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $378,798
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850247

## Citation

> US National Institutes of Health, RePORTER application 9850247, Impact of IL-1 signaling on hematopoietic stem cell function and emergence of clonal hematopoiesis. (5R01DK119394-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9850247. Licensed CC0.

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