title: 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, 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 α-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.
authors.forename: Curtis J
authors.initials: CJ
authors.lastname: Henry
authors.forename: Matias
authors.initials: M
authors.lastname: Casás-Selves
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.forename: Vadym
authors.initials: V
authors.lastname: Zaberezhnyy
authors.forename: Leila
authors.initials: L
authors.lastname: Aghili
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Daniel
authors.forename: Linda
authors.initials: L
authors.lastname: Jimenez
authors.forename: Tania
authors.initials: T
authors.lastname: Azam
authors.forename: Eoin N
authors.initials: EN
authors.lastname: McNamee
authors.forename: Eric T
authors.initials: ET
authors.lastname: Clambey
authors.forename: Jelena
authors.initials: J
authors.lastname: Klawitter
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Serkova
authors.forename: Aik Choon
authors.initials: AC
authors.lastname: Tan
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: James
authors.initials: J
authors.lastname: DeGregori
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D055153:Stem Cell Niche / Q000235:genetics
chemical_list: C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016044:Fusion Proteins, bcr-abl