Henry, Curtis J. and Casás-Selves, Matias and Kim, Jihye and Zaberezhnyy, Vadym and Aghili, Leila and Daniel, Ashley E. and Jimenez, Linda and Azam, Tania and McNamee, Eóin N. and Clambey, Eric T. and Klawitter, Jelena and Serkova, Natalie J. and Tan, Aik Choon and Dinarello, Charles A. and DeGregori, James (2015) Aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitors. Journal of Clinical Investigation, 125 (12). pp. 4666-4680. ISSN 1558-8238

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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 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.

Item Type:	Article
Keywords:	Aging-associated inflammation; adaptive oncogenic; events; B cell progenitors;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	12573
Identification Number:	https://doi.org/10.1172/JCI83024
Depositing User:	Eoin McNamee
Date Deposited:	20 Mar 2020 11:03
Journal or Publication Title:	Journal of Clinical Investigation
Publisher:	American Society for Clinical Investigation
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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