The evolution of long-lived animals has necessitated acquisition of potent tumor suppressive mechanisms to maximize reproductive success. We hypothesize that the evolution of well-adapted stem cells has conferred resistance to oncogenic mutations, as phenotype- altering genetic/epigenetic change should typically be disadvantageous within a well-adapted cell population. Nonetheless, accumulating damage and increased inflammation with age could alter the cellular fitness of self-renewing cell populations, both by causing damage to stem cells and their niche, or by altering cell developmental programs (such as for hematopoiesis). Alterations in microenvironments together with reductions in the fitness of particular stem and progenitor cell populations will then change the adaptive landscape, selecting for specific oncogenic mutations that are adaptive within this context. Focusing on the hematopoietic system and using mouse models, proposed studies will analyze the mechanisms underlying declining B-progenitor fitness in old age, and how age-associated alterations in the adaptive landscape promote selection for particular oncogenic mutations. We will 1) determine whether observed age-associated changes in B-progenitors are due to alterations in hematopoietic stem cell lineage bias, 2) ask whether manipulation of inflammation and cytokine receptor signaling in mice can impact on aging-associated reductions in hematopoietic progenitor fitness, oncogenic adaptation and leukemogenesis, and 3) dissect the molecular mechanisms underlying impaired B-lymphopoiesis and increased selection for particular oncogenes in old age. These studies should reveal important links between aging, inflammation, hematopoiesis, and leukemogenesis, and could suggest strategies to reduce cancer development with advanced age.

Public Health Relevance

While it is well known that tissue function declines and cancer incidence increases in older mice and humans, the mechanisms underlying these associations are largely unknown. Current paradigms focus on how mutations in key genes controlling cell proliferation contribute to the evolution of cancer. With the studies proposed in this application, we will investigate how the overall health of stem/progenitor cell populations and their resident tissues contributes to the prevention of malignancy. These studies should define novel links between aging, impaired hematopoiesis, and hematopoietic malignancies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Molecular and Cellular Hematology (MCH)
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Howcroft, Thomas K
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University of Colorado Denver
Schools of Medicine
United States
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Yadav, Vinod Kumar; DeGregori, James; De, Subhajyoti (2016) The landscape of somatic mutations in protein coding genes in apparently benign human tissues carries signatures of relaxed purifying selection. Nucleic Acids Res 44:2075-84
Rozhok, Andrii I; Salstrom, Jennifer L; DeGregori, James (2016) Stochastic modeling reveals an evolutionary mechanism underlying elevated rates of childhood leukemia. Proc Natl Acad Sci U S A 113:1050-5
Fleenor, Courtney J; Higa, Kelly; Weil, Michael M et al. (2015) Evolved Cellular Mechanisms to Respond to Genotoxic Insults: Implications for Radiation-Induced Hematologic Malignancies. Radiat Res 184:341-51
Henry, Curtis J; Sedjo, Rebecca L; Rozhok, Andrii et al. (2015) Lack of significant association between serum inflammatory cytokine profiles and the presence of colorectal adenoma. BMC Cancer 15:123
Rozhok, Andrii I; Wahl, Geoffrey M; DeGregori, James (2015) A Critical Examination of the ""Bad Luck"" Explanation of Cancer Risk. Cancer Prev Res (Phila) 8:762-4
Henry, Curtis J; Casás-Selves, Matias; Kim, Jihye et al. (2015) Aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitors. J Clin Invest 125:4666-80
Fleenor, Courtney Jo; Rozhok, Andrii Ivan; Zaberezhnyy, Vadym et al. (2015) Contrasting roles for C/EBPα and Notch in irradiation-induced multipotent hematopoietic progenitor cell defects. Stem Cells 33:1345-58
Rozhok, Andrii I; DeGregori, James (2015) Toward an evolutionary model of cancer: Considering the mechanisms that govern the fate of somatic mutations. Proc Natl Acad Sci U S A 112:8914-21
Ostrow, Sheli L; Barshir, Ruth; DeGregori, James et al. (2014) Cancer evolution is associated with pervasive positive selection on globally expressed genes. PLoS Genet 10:e1004239
Rozhok, Andrii I; Salstrom, Jennifer L; DeGregori, James (2014) Stochastic modeling indicates that aging and somatic evolution in the hematopoetic system are driven by non-cell-autonomous processes. Aging (Albany NY) 6:1033-48

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