# Project 3 - Transcriptional and epigenetic heterogeneity of stem/progenitor cells

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $487,068

## Abstract

PROJECT SUMMARY
 Hematopoiesis has been considered an ordered process of blood cell formation from a strict hierarchy;
however, it is now clear that intrinsic and extrinsic cellular forces influence a complex cellular ecosystem of
differentiation. While recurrent mutations cause cell autonomous disruptions in pre-leukemic settings like clonal
hematopoiesis of indeterminate potential (CHIP) and myelodysplastic syndrome (MDS), clonal selection is also
dependent on extrinsic forces in the microenvironment like inflammation. In this context, understanding how
perturbations in pre-malignant clones respond to pro-inflammatory factors becomes fundamental in therapeutic
advancement. Our project seeks to establish a molecular and cellular framework for characterization of clonal
and inflammatory hematopoiesis at single-cell resolution. We have found that alterations in mature innate
immune cells contribute to a perturbed inflammatory environment, and more specifically factors that promote
clonal expansion of CHIP mutant clones through differential activation of intracellular signlaing. Based on our
preliminary data, we propose that this unique cytokine signaling network mediates cellular function and more so
cellular metabolism specifically in mutant stem cells. The same activation in wild-type stem cells promotes
differentiation and proliferation, with loss of stemness. Our research identified Signal Transducer And Activator
Of Transcription 3 (STAT3) as one of the major intracellular signals mediating CHIP clonal function. In ongoing
studies, we will to define STAT3 specific mechanisms of clonal cell maintenance. We propose to define how
cytokine signaling pathways mediate clonal expansion (Aim 1). We will characterize the function and
transcriptional characteristics of hematopoietic stem and progenitor cells using CHIP mutant pre-clinical models
following induction and perturbation to define the molecular drivers for maintenance of transformed
hematopoietic stem cells during inflammation (Aim 2). These experiments will define new regulatory networks
by establishing and linking cytokine to active signaling and cellular metabolism. These results will provide the
basis for studies to understand how inflammation during clonal hematopoiesis regulates mitochondrial
metabolism for a selective advantage. These findings will allow us to exploit these interactions to impede pre-
malignant clones by altering the marrow microenvironment and targeting signaling axis and cellular metabolism
(Aim 3). Moving forward, these findings could lead to therapeutic interventions for improved cellular response
mitigating CHIP and changing outcomes in hematological disease.

## Key facts

- **NIH application ID:** 10840866
- **Project number:** 5P01HL131477-07
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** DANIEL G TENEN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $487,068
- **Award type:** 5
- **Project period:** 2017-04-07 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10840866

## Citation

> US National Institutes of Health, RePORTER application 10840866, Project 3 - Transcriptional and epigenetic heterogeneity of stem/progenitor cells (5P01HL131477-07). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10840866. Licensed CC0.

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