IFN-γ directly inhibits murine B-cell precursor leukemia-initiating cell proliferation early in life
IFN-γ directly inhibits murine B-cell precursor leukemia-initiating cell proliferation early in life
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DOI：
10.1002/eji.201646806
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发表时间：
2017-05-01
影响因子：
5.4
通讯作者：
Reid, Gregor S. D.
中科院分区：
文献类型：
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作者：
Fidanza, Mario;Seif, Alix E.;Reid, Gregor S. D.
早期免疫环境被认为是儿童急性淋巴细胞白血病（ALL）发展的调节因子，感染与ALL风险的显著变化相关。此外，包括IL-10和IFN-γ在内的几种细胞因子基因的多态性与白血病的发生有关。然而，这些影响的机制和时间仍然未知。在这里，我们使用E mu-ret转基因小鼠模型的B细胞前体急性淋巴细胞白血病评估的影响，IFN-γ的白血病起始细胞的早期生活负担。IFN-γ活性的缺乏导致生命早期白血病起始细胞的数量增加，并与白血病的加速发作有关。IFN-γ敲除小鼠的白血病起始细胞具有降低的细胞因子信号传导抑制因子（SOCS-1）表达，对IFN-γ显著更敏感，并且比其野生型对应物在体内表现出更快速的扩增。然而，在完全转化的IFN-γ敲除白血病细胞中，对这种抑制途径的敏感性丧失。这些结果表明IFN-γ对ALL进展的影响可能不是通过选择新生转化细胞介导的，而是通过一般SOCS介导的B细胞前体增殖的减少。因此，虽然细胞因子水平可能会影响白血病在疾病进展过程中的多个点，我们的研究表明，一个显着的基础，感染无关的细胞因子的生产白血病的早期影响。
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 E mu-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.