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

Curtis J. Henry, Matias Casás-Selves, Jihye Kim, Vadym Zaberezhnyy, Leila Aghili, Ashley E. Daniel, Linda Jimenez, Tania Azam, Eoin N. McNamee, Eric T. Clambey, Jelena Klawitter, Natalie J. Serkova, Aik Choon Tan, Charles A. Dinarello, James DeGregori

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Abstract

The incidence of cancer is higher in the elderly; however, many of the underlying mechanisms for this association remain unexplored. Here, we have shown that B cell progenitors in old mice exhibit marked signaling, gene expression, and metabolic defects. Moreover, B cell progenitors that developed from hematopoietic stem cells (HSCs) transferred from young mice into aged animals exhibited similar fitness defects. We further demonstrated that ectopic expression of the oncogenes BCR-ABL, NRASV12, or Myc restored B cell progenitor fitness, leading to selection for oncogenically initiated cells and leukemogenesis specifically in the context of an aged hematopoietic system. Aging was associated with increased inflammation in the BM microenvironment, and induction of inflammation in young mice phenocopied aging-associated B lymphopoiesis. Conversely, a reduction of inflammation in aged mice via transgenic expression of á-1-antitrypsin or IL-37 preserved the function of B cell progenitors and prevented NRASV12-mediated oncogenesis. We conclude that chronic inflammatory microenvironments in old age lead to reductions in the fitness of B cell progenitor populations. This reduced progenitor pool fitness engenders selection for cells harboring oncogenic mutations, in part due to their ability to correct aging-associated functional defects. Thus, modulation of inflammation-A common feature of aging-has the potential to limit aging-associated oncogenesis.

Original languageEnglish
Pages (from-to)4666-4680
Number of pages15
JournalJournal of Clinical Investigation
Volume125
Issue number12
DOIs
Publication statusPublished - 2015 Dec

ASJC Scopus subject areas

  • Medicine(all)

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    Henry, C. J., Casás-Selves, M., Kim, J., Zaberezhnyy, V., Aghili, L., Daniel, A. E., Jimenez, L., Azam, T., McNamee, E. N., Clambey, E. T., Klawitter, J., Serkova, N. J., Tan, A. C., Dinarello, C. A., & DeGregori, J. (2015). Aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitors. Journal of Clinical Investigation, 125(12), 4666-4680. https://doi.org/10.1172/JCI83024