Aberrant activation of Wnt/β-catenin signaling pathway is essential for the development of AML; however, the mechanistic basis for this dysregulation is unclear. PRL-3 is an oncogenic phosphatase implicated in the development of LSCs. Here, we identified Leo1 as a direct and specific substrate of PRL-3. Serine-dephosphorylated form of Leo1 binds directly to β-catenin, promoting the nuclear accumulation of β-catenin and transactivation of TCF/LEF downstream target genes such as cyclin D1 and c-myc. Importantly, overexpression of PRL-3 in AML cells displayed enhanced sensitivity towards β-catenin inhibition in vitro and in vivo, suggesting that these cells are addicted to β-catenin signaling. Altogether, our study revealed a novel regulatory role of PRL-3 in the sustenance of aberrant β-catenin signaling in AML. PRL-3 may serve as a biomarker to select for the subset of AML patients who are likely to benefit from treatment with β-catenin inhibitors. Our study presents a new avenue of cancer inhibition driven by PRL-3 overexpression or β-catenin hyperactivation.

中文翻译：

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在急性髓细胞性白血病中，PRL-3磷酸酶对β-catenin的非规范激活。

Wnt /β-catenin信号通路的异常激活对AML的发展至关重要。但是，这种失调的机制基础尚不清楚。PRL-3是一种致癌性磷酸酶，与LSC的发生有关。在这里，我们确定Leo1是PRL-3的直接和特定底物。Leo1的丝氨酸去磷酸化形式直接与β-catenin结合，促进β-catenin的核积累并激活TCF / LEF下游靶基因（如细胞周期蛋白D1和c-myc）。重要的是，在AML细胞中PRL-3的过表达在体内和体外显示出对β-catenin抑制的增强敏感性，表明这些细胞沉迷于β-catenin信号传导。总而言之，我们的研究揭示了PRL-3在维持AML中异常的β-catenin信号传导中的新型调节作用。PRL-3可以用作生物标志物，以选择可能受益于β-catenin抑制剂治疗的AML患者亚组。我们的研究提出了由PRL-3过表达或β-catenin过度活化驱动的新的癌症抑制途径。