# The role of the aged BM microenvironment in accelerating Dnmt3a mutant clonal hematopoiesis

> **NIH NIH F31** · TUFTS UNIVERSITY BOSTON · 2022 · $42,498

## Abstract

PROJECT SUMMARY
As we age, we acquire somatic mutations in our hematopoietic stem cells (HSCs), some of which can confer a
competitive advantage causing clonal HSC expansion. This clonal expansion is known as clonal
hematopoiesis (CH) and is present in 10-15% of individuals aged 70 years or older. Individuals with CH have
an increased risk of progression to hematologic malignancy compared to age-matched controls, as well as a
higher risk of coronary heart disease and ischemic stroke. While CH can be detected using next-generation
sequencing, this information is not sufficient to predict which individuals with CH will develop hematologic
malignancy, coronary heart disease, ischemic stroke, or other complications. This prediction is currently not
possible due to a lack of understanding of the mechanisms by which clonal HSC expansion and disease
development occurs. The long-term goal of my work is to improve understanding of these mechanisms and
discover interventions to stop or slow clonal HSC expansion and therefore decrease risk of CH-associated
diseases in aging individuals. The novel approach that I am taking is to focus on alterations that occur during
aging in context of the bone marrow (BM) microenvironment, which provides critical support for HSC function.
To test the concept that CH is aging-associated because of changes occurring in the aged BM
microenvironment, I will utilize an inducible mouse model of a hotspot mutation in the gene most frequently
mutated in human CH, DNA methyltransferase 3A (DNMT3A). I hypothesize that a major source of selection
pressure driving clonal HSC expansion is alterations in the aged BM microenvironment in which HSCs reside. I
will test this hypothesis by evaluating the functional impact of changes in the BM microenvironment that have
been previously described to occur generally with aging; altered cell type composition and increase in
inflammatory cytokines, on expansion of Dnmt3a-mutant (Dnmt3amut) HSCs. I will determine cell type
composition and differentiation potential of cells within young and old, Dnmt3amut and wild-type bones to
identify cell type(s) and potential mechanisms driving Dnmt3amut HSC expansion in the aged BM
microenvironment. Following this, I will functionally evaluate the effects candidate BM microenvironment cell
types isolated from aged mice on Dnmt3amut and control HSCs using in vitro co-culture. Additionally, I will
identify the cell type(s) in the BM that produce OSM, and perform ex vivo and in vivo studies inducing or
inhibiting OSM signaling to assess Dnmt3amut HSC expansion. Successful completion of this project will
determine the mechanisms by which, and extent to which, the aged BM microenvironment accelerates
development of CH. Targeting these mechanisms has high potential to prevent or reduce clonal hematopoietic
burden, and thus reduce incidence of hematologic malignancy, coronary heart disease, and ischemic stroke in
aging populations.

## Key facts

- **NIH application ID:** 10472571
- **Project number:** 5F31DK127573-03
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Logan Sari Schwartz
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $42,498
- **Award type:** 5
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10472571

## Citation

> US National Institutes of Health, RePORTER application 10472571, The role of the aged BM microenvironment in accelerating Dnmt3a mutant clonal hematopoiesis (5F31DK127573-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10472571. Licensed CC0.

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