# The Biological Consequences of Age-related Clonal Hematopoiesis

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $409,375

## Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) defined as acquisition of somatic mutations in
hematopoietic cells is a common age-related condition. The prevalence of CHIP exceeds 12% over all age
groups and nearly 50% for subjects older than 85 years. Since somatic mutations frequently affect putative
cancer drivers the malignant transformation to myelodysplasia or leukemia is an obvious concern. Even though
CHIP is relatively common, the risk of progression to clinically apparent disease is low (<1% per year) and the
exact mechanism of progression is largely unknown. Thus, the appropriate risk-stratification of patients remains
challenging. In addition to its leukemogenic potential, CHIP is also an independent risk factor of chronic
inflammation, cardiovascular disease and has been associated with inferior outcome in general population and
in patients with solid tumors. One approach to address the clinical impact of clonal hematopoiesis is to identify
and prospectively follow a large cohort of individuals with CHIP. However, this approach would require large
number of subjects and long follow-up period. While the long-term prospective studies are underway we propose
to study the natural history and clinical consequences and the mechanism of clonal expansion of CHIP in
allogeneic blood or marrow transplantation (alloBMT) setting. We have previously published that clinically silent
clones (under homeostatic conditions within the donor) expand and are selected for during the enhanced
proliferation and self-renewal required to re-establish hematopoiesis in the recipient; this implies that alloBMT
greatly hastens the natural history of CHIP, which should allow us to capture the genetic evolution, clonal
dynamics, and clinical sequelae of CHIP in an accelerated time-frame. We will 1) determine the oncogenic
potential and non-malignant adverse outcome of donor-derived CHIP in alloBMT recipients. Studying the cohort
of 1,857 bone marrow donors above the age of 40 as well as serial samples and clinical data we will better define
the oncogenic potential of low-frequency clones and distinguish true disease drivers from background genetic
events related to aging and examine the role of donor CHIP on non-malignant adverse events in alloBMT
recipients; 3) elucidate the epigenetic aberration and cellular pathway involved in clonal growth advantage; 3)
determine the impact of CHIP on the incidence of subclinical solid tumors studying nearly 10,000 females
enrolled on DETECT trial and define the role of CHIP in tumor development and progression. The
aforementioned approach will allow us 1) to better define the oncogenic potential and epigenetic aberrations in
pre-malignant clones as well as non-malignant consequences of donor CHIP in alloBMT recipients; 2) our
prospective study will not only provide an insight into the risk stratification of patients with CHIP but will also
provide a very important human model for studying clonal evolution and leukemoge...

## Key facts

- **NIH application ID:** 10348166
- **Project number:** 5R01HL156144-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Lukasz Pawel Gondek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $409,375
- **Award type:** 5
- **Project period:** 2021-02-10 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348166

## Citation

> US National Institutes of Health, RePORTER application 10348166, The Biological Consequences of Age-related Clonal Hematopoiesis (5R01HL156144-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10348166. Licensed CC0.

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