Abstract
Abstract The accumulation of oncogenic mutations over time is thought drive increased cancer incidence with age. Alternatively, we hypothesize that aging reduces cellular fitness in stem and progenitor pools, leading to increased selection for oncogenic mutations and increased cancers. We have explored how aging affects the fitness of B-progenitor cells and leukemogenesis. The fitness of B-progenitors declines with age, as defined by competitive transplantation assays. Analyses of aged B-progenitors revealed increased expression of inflammatory genes, and decreased expression of genes involved in B-lineage determination, B-cell signaling, nucleotide synthesis, and other metabolic pathways. These changes correlated with decreased interleukin-7 receptor (IL-7R) mediated signaling, reduced production of ATP and other nucleotides, and perturbations in the TCA cycle in aged B-progenitors. Decreasing IL-7R signaling and inducing inflammation in young mice impaired B-lymphopoiesis, accompanied by aging-like gene expression profiles. Importantly, neutralization of IL-7 significantly increased selection for the Bcr-Abl oncogene in B-progenitor pools, coinciding with restored signaling. Similarly, Bcr-Abl is adaptive within B-progenitor pools from aged but not young mice. These studies reveal roles for IL-7R signaling and inflammation in declining B-lymphopoiesis in old age, and demonstrate how the selection for Bcr-Abl in aged lymphopoietic backgrounds can drive leukemogenesis.
Published Version
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