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.
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.
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