# Impact of aging on the outcomes of a mouse model of chronic myeloid leukemia

> **NIH NIH UH3** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2020 · $151,531

## Abstract

Project Summary
Chronic myelogenous leukemia (CML) occurs predominantly in the elderly with a medium age at diagnosis
around 60 years. CML is caused by the oncogenic tyrosine kinase fusion gene BCR-ABL that transforms a
normal hematopoietic stem cell (HSC) into a leukemic stem cell (LSC). Several decades of CML research has
led to development of the tyrosine kinase inhibitor imatinib as the first successful targeted therapy of human
cancer. Despite the great success of imatinib in CML treatment, the drug fails to eradicate LSCs and the
disease relapses when the drug is ceased. However, the mechanisms of CML LSC drug resistance are not
well understood, which would hamper our effort in finding a cure. Mouse models of CML played a pivotal role
for illustrating roles of BCR-ABL in molecular pathogenesis of CML and for studying CML disease progression
and therapeutic interventions. However, mouse models are generated in very young mice (2 to 3 months), and
it is unknown how advanced age may influence CML in the mouse models and whether CML in older mice may
provide an advantage for modeling the human disease in response to the treatment and LSC drug resistance.
The goal of this application is to determine whether or not advanced age is an important influencing factor on
leukemia progression and pathology, response to drug treatment, as well as LSC drug resistance. Our central
hypothesis is that advanced age impacts the experimental outcomes of a mouse model of chronic myeloid
leukemia that, in human, has aging as a major risk factor. We will test this hypothesis with a well characterized
and widely used mouse model of CML by BCR-ABL transduction of BALB/c mouse bone marrow cells followed
by transplantation to lethally irradiated BALB/c recipients. We have recently identified that CML LSCs in this
mouse model reside exclusively in CD150- side population. We have discovered that protein lysine
deacetylase SIRT1 is activated by BCR-ABL transformation in HSCs and SIRT1 knockout inhibits CML
development and depletes CML LSCs in the BALB/c mouse CML model. We have shown that SIRT1 inhibition
sensitizes CML cells, particularly LSCs, to imatinib and may help eradicate LSCs. In UH2 phase of this
proposal, we will breed sufficient BALB/c mice and SIRT1 knockout mice for the feasibility and UH3 phase
studies. In UH3 phase, we will continue the maintenance of aging mice and produce additional mice for aging
and control. We will study three specific aims: 1) To determine the age impact on CML disease progression
and LSCs. 2) To determine age impact on CML LSCs in response to tyrosine kinase inhibitor treatment. 3) To
determine the impact of age on SIRT1 inhibition for eradicating CML LSCs. Successful completion of the
proposed studies will shed new insight into the effect of age on CML LSC drug resistance and may lay a
foundation for the use of aged mice for CML research for improved outcomes.

## Key facts

- **NIH application ID:** 10092787
- **Project number:** 3UH3CA213385-05S1
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** WENYONG CHEN
- **Activity code:** UH3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $151,531
- **Award type:** 3
- **Project period:** 2016-09-15 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10092787

## Citation

> US National Institutes of Health, RePORTER application 10092787, Impact of aging on the outcomes of a mouse model of chronic myeloid leukemia (3UH3CA213385-05S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10092787. Licensed CC0.

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