Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 125, Issue 12, Pages 4666-4680Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI83024
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Funding
- NIH [K01 CA160798, T32 AG000279, R01 AI15614, R01 CA180175]
- UNCF/Merck Science Initiative [2510259]
- Interleukin Foundation
- National Center for Research Resources (NCRR) [5UL1-RR025780]
- Colorado Clinical & Translational Sciences Institute (CCTSI)
- Cancer Center [P30-CA046934]
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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, NRAS(V12), 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 alpha-1-antitrypsin or IL-37 preserved the function of B cell progenitors and prevented NRAS(V12)-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.
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