| First Author | Fidanza M | Year | 2017 |
| Journal | Eur J Immunol | Volume | 47 |
| Issue | 5 | Pages | 892-899 |
| PubMed ID | 28295300 | Mgi Jnum | J:246087 |
| Mgi Id | MGI:5923221 | Doi | 10.1002/eji.201646806 |
| Citation | Fidanza M, et al. (2017) IFN-gamma directly inhibits murine B-cell precursor leukemia-initiating cell proliferation early in life. Eur J Immunol 47(5):892-899 |
| abstractText | 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-gamma, are associated with leukemia development. However, the mechanisms and timing of these influences remain unknown. Here, we use the Emu-ret transgenic mouse model of B-cell precursor ALL to assess the influence of IFN-gamma on the early-life burden of leukemia-initiating cells. The absence of IFN-gamma 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-gamma-knockout mice had reduced suppressor of cytokine signaling (SOCS-1) expression, were significantly more sensitive to IFN-gamma, and exhibited more rapid expansion in vivo than their wild-type counterparts. However, sensitivity to this inhibitory pathway was lost in fully transformed IFN-gamma-knockout leukemia cells. These results demonstrate that the influence of IFN-gamma 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. |
