title: IFN-γ directly inhibits murine B-cell precursor leukemia-initiating cell proliferation early in life.
abstract: The early-life immune environment has been implicated as a modulator of acute lymphoblastic leukemia (ALL) development in children, with infection being associated with significant changes in ALL risk. Furthermore, polymorphisms in several cytokine genes, including IL-10 and IFN-γ, are associated with leukemia development. However, the mechanisms and timing of these influences remain unknown. Here, we use the Eμ-ret transgenic mouse model of B-cell precursor ALL to assess the influence of IFN-γ on the early-life burden of leukemia-initiating cells. The absence of IFN-γ activity resulted in greater numbers of leukemia-initiating cells early in life and was associated with accelerated leukemia onset. The leukemia-initiating cells from IFN-γ-knockout mice had reduced suppressor of cytokine signaling (SOCS-1) expression, were significantly more sensitive to IFN-γ, and exhibited more rapid expansion in vivo than their wild-type counterparts. However, sensitivity to this inhibitory pathway was lost in fully transformed IFN-γ-knockout leukemia cells. These results demonstrate that the influence of IFN-γ on ALL progression may not be mediated by selection of nascent transformed cells but rather through a general SOCS-mediated reduction in B-cell precursor proliferation. Thus, while cytokine levels may influence leukemia at multiple points during disease progression, our study indicates a significant early influence of basal, infection-independent cytokine production on leukemogenesis.
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, BC, Canada.
authors.forename: Mario
authors.initials: M
authors.lastname: Fidanza
authors.affiliation: Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, PA, USA.|Division of Oncology, Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA.|Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Alix E
authors.initials: AE
authors.lastname: Seif
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, BC, Canada.
authors.forename: Sumin
authors.initials: S
authors.lastname: Jo
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, BC, Canada.
authors.forename: Amina
authors.initials: A
authors.lastname: Kariminia
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, BC, Canada.
authors.forename: Nina
authors.initials: N
authors.lastname: Rolf
authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Sly
authors.affiliation: Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, PA, USA.|Division of Oncology, Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, USA.|Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
authors.affiliation: Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, BC, Canada.|Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Gregor S D
authors.identifier: 0000-0002-7567-3424
authors.initials: GSD
authors.lastname: Reid
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology*; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D007371:Interferon-gamma
keywords: Acute lymphoblastic leukemia; IFN-γ; Pediatric; Preleukemia; SOCS-1