# Aberrant glycolysis as a driver of mutant HSPC expansion in clonal hematopoiesis

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $425,335

## Abstract

PROJECT SUMMARY / ABSTRACT
The objective of this proposal is to identify new approaches for targeting clonal hematopoiesis (CH). CH is
characterized by selective expansion of hematopoietic stem and progenitor cell (HSPC) clones harboring
mutations in genes such as TET2 and DNMT3A. These HSPC in turn produce pathogenic mutant myeloid cells
that can contribute to several aging-related co-morbidities including cardiovascular disease (CVD) and all-cause
mortality. An expanded mutant HSPC pool may also contribute to increased risk of hematological malignancies.
CH prevalence is significantly elevated in the elderly and individuals with prior genotoxic exposures, smoking
history, and/or chronic inflammatory disease. These conditions are associated with chronically perturbed
physiological homeostasis, characterized by hyper-inflammation. Understanding the mechanism(s) promoting
the selective expansion of mutant HSPC is crucial for prioritizing therapeutic targets that can suppress CH.
A central premise of our application is that that CH arises from a targetable interplay between inflammatory
signals and altered metabolic programming that supports the energetic needs and thereby the preferential
expansion of CH HSPC. Using the mouse as a model representing key features of human CH, our preliminary
data show that CH HSPC exhibit increased levels of the transcription factor Hif-1 aberrant glycolytic
metabolism and increased ATP production relative to wild-type HSPC. We find that inflammatory cytokines,
particularly IL-1 strongly potentiates CH HSPC expansion, glycolytic metabolism and Hif-1 activity. Strikingly,
treatment of CH mice with OLT-1177, an NLRP3 inflammasome inhibitor that prevents cleavage and activation
of IL-1 potently suppresses CH. We hypothesize that CH is the result of an interdependent mechanism in which
NLRP3-mediated IL-1 production potentiates Hif-1 and downstream glycolytic activity to support CH HSPC
expansion. We propose that NLRP3 inhibition disrupts this circuit, limiting expansion of CH HSPC.
To address the mechanism, we propose two Specific Aims: 1) we will characterize the metabolic features of
Tet2/, Tet2+/ and Dnmt3aR878H/+ CH HSPC using in vivo mass spectrometry- and flow cytometry-based
analyses of metabolism and glucose flux. We will also identify the extent to which CH HSPC rely upon Hif-1
and glycolysis for their energetic needs; 2) we will evaluate the requirement for NLRP3 in promoting aberrant
glycolytic activity and/or preferential expansion of CH HSPC. We will use molecular genetics approaches to
assess the role and mechanism of Hif-1 and NLRP3 in regulating CH HSPC metabolism and promoting their
expansion in vivo. Using our non-conditioned adoptive BM transfer mouse model of CH, we will validate our
mechanism using pharmacological inhibition of NLRP3 with OLT-1177 and establish whether NLRP3 blockade
suppresses HSPC expansion, aberrant metabolic activity and accumulation of inflammatory immune cells ...

## Key facts

- **NIH application ID:** 10892861
- **Project number:** 5R01DK137183-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Eric M Pietras
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $425,335
- **Award type:** 5
- **Project period:** 2023-08-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10892861

## Citation

> US National Institutes of Health, RePORTER application 10892861, Aberrant glycolysis as a driver of mutant HSPC expansion in clonal hematopoiesis (5R01DK137183-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10892861. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*