# Aged tissue environments as drivers of oncogenic adaptation in hematopoiesis

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $148,694

## 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 oncogenic 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 occurring in old age are substantial contributors to oncogenesis. In
particular, inflammation increases in the bone marrow of the elderly, which contributes to impaired
hematopoiesis. Our central hypothesis is that aging-dependent increases in inflammation are
critical for enhancing selection for oncogenic mutations, and that dampening inflammation can
reduce the risk of the associated leukemias. We previously 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. Here, we will explore how microenvironmental alterations in old age promote
oncogenesis in immature hematopoietic stem and early progenitor cell (HSPC) pools at the apex
of the hematopoietic hierarchy. We propose that C/EBPα and Myc activities are key hubs for
oncogenic selection in aged bone marrow microenvironments due to their critical roles in
balancing HSPC differentiation and self-renewal. Thus, we will develop interventions to reduce
microenvironmental perturbations that deregulate C/EBPα and Myc and lead to oncogenesis in
old age. To test our hypothesis, we will pursue two aims: 1) Determine whether aging and
inflammation drive oncogenic adaptation in the HSPC compartment and 2) Identify mechanisms
underlying increased oncogenesis with aging in 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, our 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 also identify
interventions that reduce the risk of hematopoietic malignancies of old age by manipulating
inflammatory factors that promote oncogenesis in the bone marrow microenvironment.

## Key facts

- **NIH application ID:** 9872853
- **Project number:** 1R01AG066544-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** James V Degregori
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $148,694
- **Award type:** 1
- **Project period:** 2020-01-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9872853

## Citation

> US National Institutes of Health, RePORTER application 9872853, Aged tissue environments as drivers of oncogenic adaptation in hematopoiesis (1R01AG066544-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9872853. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*