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.

Public Health Relevance

Aging is highly associated with increased leukemia risk. A better understanding of how changes in bone marrow microenvironments impact leukemogenesis should be critical for the development of new prevention and treatment interventions through modulation of the tissue landscape. While we may not be able to avoid most mutations that occur during life, we should be able to modulate tissue microenvironments to reduce leukemia risk and impact.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG067584-07
Application #
10020895
Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Kerr, Candace L
Project Start
2019-09-30
Project End
2023-05-31
Budget Start
2020-06-15
Budget End
2021-05-31
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045