# Delaying age-dependent proteostasis dysfunction in hematopoietic stem cells to restrict the emergence of clonal hematopoiesis and leukemia initiation.

> **NIH NIH U01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $158,000

## Abstract

ABSTRACT
This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-
23-045. The goal of the parent proposal is to understand how loss of protein homeostats (proteostasis) in aging
blood-forming hematopoietic stem cells (HSCs) applies a selective pressure that promotes leukemia initiation.
Loss of proteostasis is one of the least understood hallmarks of aging, particularly as it relates to malignant
transformation. As an organism ages, misfolded proteins can accumulate in post-mitotic cells, or in cells that are
largely quiescent. HSCs are particularly susceptible to a loss of proteostasis. Adult HSCs have low rates of
protein synthesis relative to more frequently dividing lineage-committed blood progenitors. A low protein
synthesis rate helps maintain proteostasis by preventing the biogenesis of misfolded proteins, and it is required
to maintain adult HSC self-renewal capacity. However, we discovered that aged HSCs experience significant
protein stress in vivo, and proteostasis must be actively maintained through changes in gene expression and
stress-response pathways to sustain HSC self-renewal activity and longevity. These data indicate that aged
HSCs must actively maintain proteostasis to remain functional, and loss of proteostasis may create a selective
pressure that promotes clonal hematopoiesis and leukemia initiation. Based on these data, we hypothesize that
a loss of proteostasis and pressure to maintain proteostasis in aging HSCs promotes clonal hematopoiesis and
acute myeloid leukemia (AML) initiation in older adults. In the parent award (U01CA267031), we set out to
determine if proteostasis disruption promotes clonal hematopoiesis and AML initiation during aging. Now, in
collaboration with Dr. Eric Bennett, we generated a new genetic mouse model (Rps23K60R) with a mutation in the
decoding region of the ribosome that enhances translation fidelity and mitigates proteostasis disruption in aging
HSCs. These animals are viable, grossly normal, fertile and can live beyond 3 years of age and have functional
HSCs as determined in transplantation studies. Using this new mouse model, our goal is to extend our parental
award to directly test if preserving proteostasis in HSCs restricts the emergence of clonal hematopoiesis and
impedes AML initiation. We will test whether delaying proteostasis disruption prevents clonal hematopoiesis and
AML initiation during aging in the setting of a Dnmt3aR878H mutation. We will also examine if enhanced translation
fidelity in Rps23K60R animals impedes AML initiation in aging HSCs using Dnmt3aR878H mutant animals with a
cooperating NrasG12D mutation. Research outcomes from this supplemental research will determine if enhancing
translation fidelity restrains the emergence of clonal hematopoiesis and reduces the incidence of AML in older
animals. These studies will open new lines of investigation into a previously unappreciated link between age-
related proteosta...

## Key facts

- **NIH application ID:** 10831320
- **Project number:** 3U01CA267031-03S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Jeffrey Alan Magee
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $158,000
- **Award type:** 3
- **Project period:** 2021-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831320

## Citation

> US National Institutes of Health, RePORTER application 10831320, Delaying age-dependent proteostasis dysfunction in hematopoietic stem cells to restrict the emergence of clonal hematopoiesis and leukemia initiation. (3U01CA267031-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10831320. Licensed CC0.

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