Abstract 4982: Aging-associated alterations in IL-7 receptor signaling and inflammation promote declining B-lymphopoiesis and increased leukemogenesis

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL The incidences of most cancers increase with age. Thus age is thought to be the single most important prognostic factor for the development of many cancers. Current dogma attributes the association between aging and cancers to the accumulation of oncogenic mutations, which is thought to limit initiation and progression of cancer. Alternatively, we hypothesize that aging-associated functional decline caused by cell autonomous and non-autonomous mechanisms is likely to reduce the fitness of stem and progenitor cell populations. This reduction in fitness should be conducive for increased selection of adaptive oncogenic mutations which can at least partially alleviate fitness defects, thereby promoting the initiation of cancers. Using competitive bone marrow transplantation (BMT) mouse models, microarray analysis, cellular signaling and metabolic assays, we have explored how aging affects the fitness of hematopoietic progenitor cells and subsequently leukemogenesis. Using BMT experiments we have found that Bcr-Abl becomes adaptive within B-cell progenitor pools from aged but not young mice. Microarray analysis of aged B-progenitors revealed aberrant gene expression relative to young progenitors, including increased inflammation-associated genes, and decreased expression of B-lineage genes, critical metabolic genes (including for nucleotide synthesis), and genes downstream of IL-7 receptor (IL-7R) signaling essential for B-cell development. Indeed, we observed decreased kinase signaling downstream of the IL-7R. Aging also led to decreased metabolism (including reduced NADH consumption and ATP production) and alterations in TCA cycle intermediates in B-cell progenitors. These aging-associated effects were recapitulated in young mice by reducing signaling through the IL-7R or increasing inflammation (both are associated with advanced age in humans and mice). Moreover, both decreased IL-7R signaling and increased inflammation in young mice led to decreased B-cell lymphopoiesis, and altered expression of metabolic genes (which were also decreased in aged progenitors). Importantly, neutralization of IL-7 was sufficient to promote selection for Bcr-Abl in young B-cell progenitors. These studies indicate that a significant part of the aging-associated decline in B-cell lymphopoiesis results from reduced IL-7R signaling and increased inflammation. Furthermore, our results 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. The findings from this work could potentially be used in the treatment of aging-associated cancers of various etiological origins. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4982. doi:1538-7445.AM2012-4982