# Amy Briggs Diversity Supplement R01AG067584

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $30,554

## Abstract

The risk of most cancers, including leukemias, increases exponentially as we age, with
over 90% of cancers occurring after the age of 50. This association has been primarily ascribed
to the gradual accumulation of mutations throughout life. We contend that the contribution of
mutations (while necessary) is not sufficient to explain the role of aging in the development of
leukemias and other cancers. Just as species evolution has been driven by environmental
changes that select for adaptive phenotypes in populations, we propose that the changes in our
tissues known to occur in old age are substantial contributors to oncogenesis. Inflammation and
senescent cells increase in the bone marrow of the elderly, which along with other changes
contribute to impaired hematopoiesis. In the current funding period, we have used mouse models
to show that the aged and inflammatory bone marrow microenvironment reduces the fitness of B-
cell progenitors, promoting selection for particular adaptive oncogenic events, leading to
increased leukemogenesis in these contexts. Here, we will explore how changes in hematopoietic
stem and early progenitor cell (HSPC) pools driven by microenvironmental alterations in old age
influence selection on oncogenic events known to initiate acute myeloid leukemias. We will also
develop interventions to reduce microenvironmental perturbations and associated oncogenesis
in old age. Our central hypothesis is that aging-dependent increases in inflammation and
senescent cells are critical for enhancing selection for oncogenic mutations that occur throughout
life, and that dampening inflammation and/or removing senescent cells can reduce the risk of the
associated leukemias. To test our hypothesis, we will pursue two aims: 1) Determine how aging,
inflammation and senescence influence oncogenic adaptation in the HSPC compartment and 2)
Identify the mechanisms underlying increased oncogenesis in aged HSPC pools.
 By determining whether and how microenvironmental changes impact HSPC fitness and
thus oncogenic adaptation in old age, these results could provide a new explanation for links
between aging and leukemia risk. In all, proposed studies could provide answers for fundamental
questions: Why do we get more leukemias as we age? Why are particular oncogenic mutations
selected for in the bone marrow of the elderly? Can we alter aging-associated positive selection
for oncogenic events and thus reduce leukemia risk? These studies could suggest interventions
that can reduce the risk of hematopoietic malignancies of old age by manipulating specific factors
in the bone marrow microenvironment.

## Key facts

- **NIH application ID:** 10273522
- **Project number:** 3R01AG067584-07S1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** James V Degregori
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $30,554
- **Award type:** 3
- **Project period:** 2019-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10273522

## Citation

> US National Institutes of Health, RePORTER application 10273522, Amy Briggs Diversity Supplement R01AG067584 (3R01AG067584-07S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10273522. Licensed CC0.

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