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 November 9, 2015
Citation Information: J Clin Invest. 2015;125(12):4666-4680. https://doi.org/10.1172/JCI83024.
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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 3

Increased inflammation in the BM with age coincides with decreased expression of genes regulating cell-cycle progression in B progenitors.

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Increased inflammation in the BM with age coincides with decreased expre...
(A) PCA of the microarray data was generated using the Partek Genomics Suite. (B) Gene expression profiles from the microarray analysis performed on B cell progenitors isolated from young and old mice were analyzed by GSEA for the expression of genes regulated by E2F and MYC and of those involved in inflammatory processes. (C and D) BM aspirates were collected from young (Y; 2-month-old), middle-aged (M; 14-month-old), and old (O; 24-month-old) mice, and IL-6 (C) and TNF-α (D) levels were determined using ELISA. Values represent the mean ± SEM of 2 independent experiments, with more than 6 mice per age group. (E) Network analysis of the microarray data was performed using IPA software, which identified TNF-α as an important cytokine that increases in aged B progenitors. (F) Heatmap showing a subset of the inflammatory genes shown in B. (G) Pro–B cell progenitors from young (2-month-old) and old (24-month-old) mice were sorted, and expression levels of inflammatory genes (Tnfa, Ifnz, and Ifi27) or of those regulated by inflammation (e.g., Muc5b) were determined by qPCR. (H) Expression levels of TNF-α in sorted young or old pro–B cells expressing vector or oncogenic BCR-ABL, NRASV12, or Myc (all GFP+) were determined using qPCR. Values in G and H represent the mean ± SEM of 4 independent experiments, with more than 10 mice per age group. #P < 0.001, by Student’s t test relative to young controls. ND, not determined.