# Clonal Hematopoiesis, Aging and Genome Stability in PPM1D Mutants

> **NIH NIH U01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $120,000

## Abstract

ABSTRACT
Aging of many tissues is accompanied by accumulation of mutations, which are thought to
contribute to decline of tissue function. In the hematopoietic system, hematopoietic stem and
progenitor cells (HSPCs) with somatic mutations have differential abilities to contribute to blood
production, and over time, some of them exhibit enhanced contribution to the blood in a
condition termed “clonal hematopoiesis” (CH). Somatic mutations in CH are recurrently found in
about 20 genes, but the mechanisms through which these mutations give particular clones an
advantage are poorly understood. Mutations in PPM1D, which encodes a protein phosphatase
that regulates stress and DNA damage responses, are found in about 5% of individuals with
CH. CH-associated PPM1D mutations invariably truncate the protein and result in a hyperactive
phosphatse. We hypothesize that hyperactive PPM1D provides an advantage to HSPCs via
enhancing their survival after specific types of DNA damage. Here, we will focus on the behavior
of PPM1D mutant HSPCs in a mouse model in the context of age and genotoxic stressors, and
also examine the alterations in DNA repair pathways in PPM1D-mutant cells. First, we will
examine clonal hematopoiesis in the context of aging and genotoxic stress in mice. Second, we
will examine how mechanisms of DNA repair are altered in the context of PPM1D mutations.
Overall, this study will expand our understanding of the mechanisms that give rise to clonal
hematopoiesis, and in particular, the fitness landscapes and cellular mechanisms that promote
clonal expansion, to establish a paradigm of context-specific clonal hematopoiesis. This insight
will ultimately contribute to our understanding of the clinical implications and prognostic
significance of clonal hematopoiesis.

## Key facts

- **NIH application ID:** 9942391
- **Project number:** 5U01CA236972-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** MARGARET A. GOODELL
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $120,000
- **Award type:** 5
- **Project period:** 2019-06-04 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942391

## Citation

> US National Institutes of Health, RePORTER application 9942391, Clonal Hematopoiesis, Aging and Genome Stability in PPM1D Mutants (5U01CA236972-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9942391. Licensed CC0.

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