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

Cancer incidence increases in the elderly, although the underlying reasons for this association are unknown. We show that B-progenitors in old mice exhibit profound signaling and metabolic defects, and that expression of BCR-ABL, NRASV12 and MYC reverses these fitness defects, leading to selection of oncogenically-initiated cells and leukemogenesis in old hematopoietic backgrounds. Aging is associated with increased inflammation in the BM microenvironment, and inducing inflammation in young mice phenocopies aging B-lymphopoiesis. Importantly, reducing inflammation in aged mice preserves the function of B-progenitors and prevents NRasV12-mediated oncogenesis. We conclude that chronic microenvironments in old age lead to reductions in the fitness of hematopoietic stem and progenitor cell populations. This reduced progenitor pool fitness leads to selection for cells harboring oncogenic mutations in part due to their ability to correct aging-associated functional defects.

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Henry CJ, Casás-Selves M, Kim J, Zaberezhnyy V, Aghili L, Daniel AE, Jimenez L, Azam T, McNamee EN, Clambey ET, Klawitter J, Serkova NJ, Tan AC, Dinarello CA, DeGregori J