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 language | English |
|---|---|
| Pages (from-to) | 4666-4680 |
| Number of pages | 15 |
| Journal | Journal of Clinical Investigation |
| Volume | 125 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 2015 Dec 1 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Medicine(all)
Cite this
Aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitors. / Henry, Curtis J.; Casás-Selves, Matias; Kim, Jihye; Zaberezhnyy, Vadym; Aghili, Leila; Daniel, Ashley E.; Jimenez, Linda; Azam, Tania; McNamee, Eoin N.; Clambey, Eric T.; Klawitter, Jelena; Serkova, Natalie J.; Tan, Aik-Choon; Dinarello, Charles A.; DeGregori, James.
In: Journal of Clinical Investigation, Vol. 125, No. 12, 01.12.2015, p. 4666-4680.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Aging-associated inflammation promotes selection for adaptive oncogenic events in B cell progenitors
AU - Henry, Curtis J.
AU - Casás-Selves, Matias
AU - Kim, Jihye
AU - Zaberezhnyy, Vadym
AU - Aghili, Leila
AU - Daniel, Ashley E.
AU - Jimenez, Linda
AU - Azam, Tania
AU - McNamee, Eoin N.
AU - Clambey, Eric T.
AU - Klawitter, Jelena
AU - Serkova, Natalie J.
AU - Tan, Aik-Choon
AU - Dinarello, Charles A.
AU - DeGregori, James
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84948798306&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84948798306&partnerID=8YFLogxK
U2 - 10.1172/JCI83024
DO - 10.1172/JCI83024
M3 - Article
C2 - 26551682
AN - SCOPUS:84948798306
VL - 125
SP - 4666
EP - 4680
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 12
ER -