PU.1-mediated upregulation of CSF1R is crucial for leukemia stem cell potential induced by MOZ-TIF2.
PU.1-mediated upregulation of CSF1R is crucial for leukemia stem cell potential induced by MOZ-TIF2.
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白血病和其他癌症拥有自我更新的干细胞，有助于维持癌症。癌症干细胞根除被认为是成功的抗癌治疗的关键。通过引入白血病相关单核细胞白血病锌指(MoZ)-TIF2融合蛋白诱导的急性髓系白血病(AML)模型，我们证明了通过去除白血病干细胞可以治愈AML。MoZ融合蛋白与PU.1相互作用，刺激巨噬细胞集落刺激因子受体(M-CSFR，又称CSF1R/c-FMS/CD115)的表达。对PU.1缺陷小鼠的分析表明，PU.1对于MoZ-TIF2建立和维持AML干细胞是必不可少的。高水平表达CSF1R的细胞(CSF1R高细胞)，而不表达低水平CSF1R的细胞(CSF1Rlow/−细胞)，显示出强大的白血病启动活性。使用由CSF1R启动子控制的表达药物诱导自杀基因的转基因小鼠，通过切除CSF1RHigh细胞治愈AML。CSF1R缺陷小鼠急性髓系白血病的诱导受到抑制。CSF1R抑制剂延缓了MoZ-TIF2诱导的白血病的进展。因此，CSF1R高表达细胞含有白血病干细胞，PU1介导的CSF1R表达上调可能是治疗Moz白血病的有用靶点。
Leukemias and other cancers possess self-renewing stem cells that help to maintain the cancer. Cancer stem cell eradication is thought to be critical for successful anti-cancer therapy. Using an acute myeloid leukemia (AML) model induced by introducing the leukemia-associated monocytic leukemia zinc finger (MOZ)-TIF2 fusion protein, we show here that AML can be cured by the ablation of leukemia stem cells. The MOZ-fusion proteins interacted with PU.1 to stimulate the expression of macrophage-colony stimulating factor receptor (M-CSFR, also called CSF1R/c-FMS/CD115). Analysis using PU.1-deficient mice demonstrated that PU.1 was essential for MOZ-TIF2 to establish and maintain AML stem cells. Cells expressing high levels of CSF1R (CSF1Rhigh cells), but not those expressing low levels of CSF1R (CSF1Rlow/− cells), showed potent leukemia-initiating activity. Using transgenic mice expressing a drug-inducible suicide gene controlled by the CSF1R promoter, AML was cured by ablation of the CSF1Rhigh cells. Induction of AML was suppressed in CSF1R-deficient mice. CSF1R inhibitors slowed the progress of MOZ-TIF2–induced leukemia. Thus, CSF1Rhigh cells contain leukemia stem cells, and the PU.1-mediated upregulation of CSF1R may be a useful therapeutic target for MOZ leukemia.
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