Declining lymphoid progenitor fitness promotes aging-associated leukemogenesis

Abstract

Aging is associated with the functional decline of cells, tissues, and organs. At the same time, age is the single most important prognostic factor in the development of most human cancers, including chronic myelogenous and acute lymphoblastic leukemias initiated by Bcr-Abl oncogenic translocations. Prevailing paradigms attribute the association between aging and cancers to the accumulation of oncogenic mutations over time, because the accrual of oncogenic events is thought to be the rate-limiting step in initiation and progression of cancers. Conversely, aging-associated functional decline caused by both cell-autonomous and non-cell-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 oncogenic mutations that can at least partially alleviate fitness defects, thereby promoting the initiation of cancers. We tested this hypothesis using mouse hematopoietic models. Our studies indicate that the dramatic decline in the fitness of aged B-lymphopoiesis coincides with altered receptor-associated kinase signaling. We further show that Bcr-Abl provides a much greater competitive advantage to old B-lymphoid progenitors compared with young progenitors, coinciding with restored kinase signaling pathways, and that this enhanced competitive advantage translates into increased promotion of Bcr-Abl-driven leukemias. Moreover, impairing IL-7-mediated signaling is sufficient to promote selection for Bcr-Ablexpressing B progenitors. These studies support an unappreciated causative link between aging and cancer: increased selection of oncogenic mutations as a result of age-dependent alterations of the fitness landscape.A lthough hematopoietic stem cells (HSCs) are capable of maintaining hematopoiesis throughout the life of mice and humans, HSCs and progenitor cells show significant age-related functional decline (1). In mice, aging-associated defects in B and T lymphopoiesis are particularly apparent, which can be attributed to both cell-intrinsic and -extrinsic effects of aging (2-6). B-cell development in old mice is severely impaired starting at early B-cell progenitor (EBP) and pro-B cell stages.Age is the largest risk factor for cancer development in mammals. The incidence of most human cancers rises exponentially with age, dramatically accelerating after midlife (7,8). Cancer progression represents a process of somatic evolution, whereby a single initially WT cell gives rise to a highly complex tumor containing populations of cells harboring large numbers of genetic and epigenetic alterations. This evolutionary process is driven by two components: diversification of heritable types through acquisition of genetic and epigenetic changes and selection for those cells that harbor mutations increasing cell fitness (wherein "fitness" is a measure of the ability of a cell of a certain genotype to pass this genotype to subsequent cell generations, as governed by competition for similar niches). Predominant paradigms attr...

Aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitors

“…The aging-associated decreases in the expression of the key purine synthesis genes hypoxanthine-guanine phosphoribosyltransferase (Hprt) and guanine monophosphate synthase (Gmps) were confirmed using quantitative PCR (qPCR) analysis in sorted pro-B cell populations ( Figure 1B). IL-7 signaling decreases with age in B cell progenitors (16,37). Similar to previous reports (38), inhibiting IL-7R signaling by injecting mice with IL-7 neutralizing Abs (αIL-7) significantly decreased the expression of Pax5 in pro-B cells ( Figure 1C).…”

“…Thus, provision of the oncogenic drivers is insufficient to induce leukemias, as the leukemic potential of the oncogenic mutations is only fully realized in the aged hematopoietic context. Notably, we have previously shown that the differential ability of BCR-ABL to induce leukemias in young and old hematopoietic backgrounds does not require an intact adaptive immune system (16).…”

“…Inflammation-inducing and IL-7-neutralizing experiments IL-7 neutralization experiments were performed as previously described (16). In these experiments, IL-7-neutralizing Abs were injected at a dose of 0.5 mg/mouse every 4 days until the experiment was terminated.…”

“…Intracellular staining. Intracellular cytokine staining was performed as previously described (16). The following BD Biosciences PE-conjugated Abs were used: p-STAT3 (P-Y705, catalog 612569), p-STAT5 (P-Y694, catalog 612567), p-ERK1/2 (P-T202/P-Y204, catalog 612566), and control (rat IgG2b, catalog 556925).…”

“…Additional studies have indicated that the aged BM microenvironment can contribute to reductions in B lymphopoiesis (14,15). Notably, we have previously shown that declining B lymphoid progenitor fitness in old mice promotes selection for the BCR-ABL oncogene due to its ability to correct aging-associated defects in cell signaling (16).…”