Current paradigms attribute the association between aging and cancers to the accumulation of oncogenic mutations. Alternatively, we hypothesize that aging-associated reductions in the fitness of stem and progenitor cell populations should be conducive for increased selection of adaptive oncogenic mutations which can partially restore fitness, thereby promoting the initiation of cancers. We have explored how aging affects B-cell progenitor fitness and subsequently leukemogenesis. Here we show that IL-7 receptor (IL-7R) signaling is defective in aged B-cell progenitors leading to reduced phospho-STAT5 and Akt levels. Aged B-cell progenitors also exhibit altered expression of IL-7R regulated genes, including reduced Pax5, Myc and HPRT, and increased TNF-α. Both decreasing IL-7R signaling and increasing inflammation phenocopied aging-associated B-lymphopoiesis defects in young mice. Decreasing IL-7R signaling also promoted selection for Bcr-Abl expressing B-cell progenitors coinciding with increased leukemogenesis in vivo. Importantly, Bcr-Abl restored defective IL-7R signaling and inflammation-induced defects in these cells. These studies elucidate how reduced IL-7R signaling and increased inflammation promote aging-associated reductions in B-lymphopoiesis. Furthermore, we show that the selection for cells harboring oncogenic mutations (such as Bcr-Abl) is increased in aged backgrounds due in part to their ability to correct aging-associated fitness defects.
- Copyright © 2013 by The American Association of Immunologists, Inc.