# PPM1D in Clonal Hematopoiesis and Malignancies

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $599,632

## Abstract

ABSTRACT
 Clonal hematopoiesis (CH) is a condition in which individual hematopoietic stem cells
(HSCs) contribute disproportionately to peripheral blood production. Individuals with CH are at
significantly greater risk of developing hematologic malignancies compared to those without CH.
Analysis of CH-associated leukemias has recently revealed recurrent mutations in a number of
cancer-associated genes, including PPM1D, which was previously not associated with leukemia
development. In addition, PPM1D mutations have been observed in patients developing
secondary leukemias after having received chemotherapy for prior non-hematopoietic solid
tumors. PPM1D encodes the Wildtype p53-Induced Phosphatase 1 (WIP1), which is
upregulated by p53 during DNA damage and acts homeostatically to dephosphorylate and
downregulate DNA damage response proteins. PPM1D mutations are generally C-terminal
truncating mutations that cause dramatic increases in WIP1 protein levels. It has been
hypothesized that PPM1D mutations enhance fitness of hematopoietic stem and progenitor cells
subjected to chemotherapeutic stress and may further contribute to malignant progression of
HSC-derived cells in the context of other driver mutations.
 The precise mechanisms by which PPM1D mutations enhance hematopoietic cell fitness
remain poorly understood. In this application we propose cellular, animal, and human patient
studies to better understand how PPM1D mutations may drive clonal hematopoiesis and
leukemogenesis with a long-term goal of testing therapeutic approaches that might target
patients with malignancies that display such mutations. We propose four specific aims that
include (1) the comparison of long term hematopoiesis and cancers in genetically engineered
mice with a germline truncating mutation in Ppm1d; (2) the use of competitive HSC transplant
experiments to analyze the fitness landscapes that impact the evolution and outcome of pre-
leukemic hematopoiesis; (3) the use of genomic screens and cellular assays to identify
pathways and elucidate functional mechanisms associated with PPM1D mutations in normal
hematopoietic cells and leukemic cells; and (4) investigation of PPM1D-associated mutation
signatures and clonal architecture of secondary leukemia and myelodysplastic syndrome cells
arising in human patients exposed to previous chemotherapy for a primary tumor. These
comprehensive studies on this newly discovered leukemia-associated oncogene may guide
choice of therapeutic agents and elucidate mechanisms underlying the evolutionary selection of
mutations that drive the progression from clonal dominance to malignancy.

## Key facts

- **NIH application ID:** 10197856
- **Project number:** 5R01CA237291-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Lawrence A. Donehower
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $599,632
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197856

## Citation

> US National Institutes of Health, RePORTER application 10197856, PPM1D in Clonal Hematopoiesis and Malignancies (5R01CA237291-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10197856. Licensed CC0.

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