# Role of therapy-related clonal hematopoiesis in anthracycline-induced cardiotoxicity

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $403,750

## Abstract

SUMMARY
The accumulation of somatic DNA mutations in driver genes within the hematopoietic system can provide a
fitness advantage to the mutant cell and thus allow for its clonal expansion. This process is referred to as clonal
hematopoiesis and leads to a situation where a substantial fraction of an individual’s blood cells are replaced by
clones with the driver gene mutation. Previous large exome sequencing studies in humans have shown that
these somatic mutations accumulate during aging and are associated with a higher rate of cardiovascular-related
deaths. Moreover, recent experimental studies support the idea that clonal hematopoiesis causally promotes
cardiovascular disease (CVD). More recently, genotoxic stresses such as radiation or chemotherapy have also
been shown to facilitate hematopoietic clonal expansion in cancer patients. Compared with age-related clonal
hematopoiesis that is mediated primarily by mutations in epigenetic regulators such as DNMT3A and TET2,
clonal hematopoiesis resulting from prior exposure to cytotoxic therapy is uniquely associated with high
frequencies of mutations in TP53 and PPM1D. This clonal selection/expansion of TP53 and PPM1D mutant
clones by cancer therapy may subsequently increase the risk of CVD, and addressing this clinically-relevant
question represents the main objective of the current proposal.
In fact,
over the past decade, the number of
cancer survivors has grown, thus there has been a paradigm shift in the approach to survivor care with a renewed
focus on maximizing non-cancer-related outcomes, such as CVD. Therefore, there is an unmet need to
understand the potential connection between cancer-therapy related clonal hematopoiesis and CVD. Thus, this
study aims to examine whether a causal connection exists between therapy-related clonal hematopoiesis and
chemotherapy-associated cardiomyopathy. As a proof-of-concept, I will test the hypothesis that TP53- and
PPM1D-mediated clonal hematopoiesis contributes to anthracycline-induced cardiomyopathy using
sophisticated animal models.

## Key facts

- **NIH application ID:** 9943767
- **Project number:** 1R01HL152174-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** KENNETH WALSH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $403,750
- **Award type:** 1
- **Project period:** 2020-06-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9943767

## Citation

> US National Institutes of Health, RePORTER application 9943767, Role of therapy-related clonal hematopoiesis in anthracycline-induced cardiotoxicity (1R01HL152174-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9943767. Licensed CC0.

---

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