Aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitors
Curtis J. Henry, … , Charles A. Dinarello, James DeGregori
Curtis J. Henry, … , Charles A. Dinarello, James DeGregori
Published December 1, 2015; First published November 9, 2015
Citation Information: J Clin Invest. 2015;125(12):4666-4680. https://doi.org/10.1172/JCI83024.
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Categories: Research Article Aging

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

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 α-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.

Authors

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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Figure 7

Reducing inflammation in aged AATtg mice suppresses selection for oncogenic NRASV12–expressing B progenitors.

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Reducing inflammation in aged AATtg mice suppresses selection for oncoge...
(A) Experimental overview. (B and C) Frequencies of young, vector-expressing (CFP+) cells (B) or young, NRASV12-expressing (GFP+) cells (C) in the peripheral blood of recipient mice were monitored for 2 months after transplantation. (D) After 2 months, mice were sacrificed, and the frequencies of NRASV12-expressing pre–B cell progenitors in the BM of recipient mice were determined by flow cytometry. LD, limit of detection. (E) Recipient pro–B cells (CD45.2+) were analyzed by flow cytometry for STAT5 and ERK activation. (F) STAT5 activation in donor pro–B cells (CD45.1+) expressing vector (CFP+) or NRASV12 (GFP+) was analyzed using flow cytometry. (G and H) Expression levels of the indicated genes in sorted donor (CD45.1+) pro–B cells expressing vector (V) or NRASV12 (RAS) were determined by qPCR . Values in B–H represent the mean ± SEM, with more than 5 mice per group. (B–E and G) #P < 0.001, by Student’s t test relative to young controls. (F and H) *P < 0.05, **P < 0.01, and #P < 0.001, by 1-way ANOVA. Ctrl, control.