The E3 ubiquitin ligase (E3) WWP1 is an oncogenic factor implicated in the maintenance of different types of epithelial cancers. The role of WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) in haematological neoplasms remains unknown. Acute myeloid leukaemia (AML) is characterized by the expansion of malignant myeloid cells blocked at different stages of differentiation. Here we report that the expression of WWP1 is significantly augmented in a large cohort of primary AML patients and in AML cell lines, compared with haematopoietic cells from healthy donors. We show that WWP1 inactivation severely impairs the growth of primary AML blasts and cell lines in vitro. In vivo, we observed a reduced leukaemogenic potential of WWP1-depleted AML cells upon transplantation into immunocompromised mice. Mechanistically, WWP1 inactivation induces the accumulation of its protein substrate p27^Kip1, which ultimately contributes to G₀/G₁ cell cycle arrest of AML blasts. In addition, WWP1 depletion triggers the autophagy signalling and reduces survival of leukaemic cells. Collectively, our findings provide molecular insights into the anti-cancer potential of WWP1 inhibition, suggesting that this E3 is a promising biomarker and druggable target in AML.

中文翻译：

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E3 泛素连接酶 WWP1 维持急性髓性白血病的生长。

E3 泛素连接酶 (E3) WWP1 是一种致癌因子，与不同类型的上皮癌的维持有关。含有 WW 结构域的 E3 泛素蛋白连接酶 1 (WWP1) 在血液肿瘤中的作用仍然未知。急性髓性白血病 (AML) 的特征是恶性髓细胞的扩张在不同分化阶段被阻断。在这里，我们报告说，与来自健康供体的造血细胞相比，WWP1 的表达在一大群原发性 AML 患者和 AML 细胞系中显着增强。我们表明 WWP1 失活严重损害了体外原发性 AML 原始细胞和细胞系的生长。在体内，我们观察到 WWP1 耗尽的 AML 细胞在移植到免疫功能低下的小鼠中后白血病发生潜力降低。机械地，^Kip1，最终导致AML 原始细胞的 G ₀ /G _{1细胞周期停滞。}此外，WWP1 消耗会触发自噬信号并降低白血病细胞的存活率。总的来说，我们的研究结果为 WWP1 抑制的抗癌潜力提供了分子见解，表明该 E3 是 AML 中一个有前途的生物标志物和可药用靶标。