IFN-γ directly inhibits murine B-cell precursor leukemia-initiating cell proliferation early in life

Eur J Immunol. 2017 May;47(5):892-899. doi: 10.1002/eji.201646806. Epub 2017 Apr 11.

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.

Keywords: Acute lymphoblastic leukemia; IFN-γ; Pediatric; Preleukemia; SOCS-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology*
  • Cell Proliferation*
  • Interferon-gamma / deficiency
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology*
  • Interferon-gamma / metabolism*
  • Lymphocyte Activation
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / immunology
  • Precursor Cells, B-Lymphoid / immunology*
  • Signal Transduction
  • Suppressor of Cytokine Signaling 1 Protein / genetics
  • Suppressor of Cytokine Signaling 1 Protein / metabolism

Substances

  • Socs1 protein, mouse
  • Suppressor of Cytokine Signaling 1 Protein
  • Interferon-gamma