IFN-[gamma] directly inhibits murine B-cell precursor leukemia-initiating cell proliferation early in life

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 Eµ-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.