# The influence of proteostasis loss in aging hematopoietic stem cells on leukemia initiation

> **NIH NIH U01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $381,271

## Abstract

ABSTRACT
The goal of this 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. This stresses the cell and can drive adaptive changes that are required to rebalance
proteostasis. 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. This helps maintain
proteostasis by preventing the biogenesis of misfolded proteins, and it is required to maintain adult HSC self-
renewal capacity. However, we have 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. In this regard, we have generated preliminary data
demonstrating that Hsf1, a critical proteostasis sensor that dynamically remodels the proteostasis network in
response to stress, is activated within aging HSCs where it is required to attenuate protein synthesis and
preserve HSC self-renewal capacity. 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. We propose two aims to test this hypothesis. In the first aim, we will use Aarssti/sti mice, which have a
defect in tRNA editing activity, to disrupt proteostasis in young and old adult mice. We will test whether
proteostasis disruption accelerates clonal hematopoiesis and AML initiation during aging in the setting of
Dnmt3aR878H and Tet2D/D mutations. In the second aim, we will test if normal age-related activation of Hsf1 creates
a permissive context for AML initiation in aging HSCs. We will conditionally delete Hsf1 in young and old adult
HSCs in the setting of a Dnmt3aR878H mutation with and without a cooperating NrasG12D mutation to determine if
it contributes to the emergence of clonal hematopoiesis and increased incidence of AML in older adults. These
studies will open new lines of investigation into a previously unappreciated link between age-related loss of
proteostasis (a hallmark of aging) and leukemia initiation. Therapies that mitigate proteostasis dysfunction could
preserve HSC clonal diversity later in life while reducing susceptibility to AML.

## Key facts

- **NIH application ID:** 10355822
- **Project number:** 1U01CA267031-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Jeffrey Alan Magee
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,271
- **Award type:** 1
- **Project period:** 2021-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10355822

## Citation

> US National Institutes of Health, RePORTER application 10355822, The influence of proteostasis loss in aging hematopoietic stem cells on leukemia initiation (1U01CA267031-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10355822. Licensed CC0.

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