文章：

急性髓系白血病中SET介导的蛋白磷酸酶2A活性调控新机制

A new regulatory mechanism of protein phosphatase 2A activity via SET in acute myeloid leukemia

原文发布日期：2020-01-08

DOI: 10.1038/s41408-019-0270-0

类型: Article

开放获取: 是

英文摘要：

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy. Although novel emerging drugs are available, the overall prognosis remains poor and new therapeutic approaches are required. PP2A phosphatase is a key regulator of cell homeostasis and is recurrently inactivated in AML. The anticancer activity of several PP2A-activating drugs (e.g., FTY720) depends on their interaction with the SET oncoprotein, an endogenous PP2A inhibitor that is overexpressed in 30% of AML cases. Elucidation of SET regulatory mechanisms may therefore provide novel targeted therapies for SET-overexpressing AMLs. Here, we show that upregulation of protein kinase p38β is a common event in AML. We provide evidence that p38β potentiates SET-mediated PP2A inactivation by two mechanisms: facilitating SET cytoplasmic translocation through CK2 phosphorylation, and directly binding to and stabilizing the SET protein. We demonstrate the importance of this new regulatory mechanism in primary AML cells from patients and in zebrafish xenograft models. Accordingly, combination of the CK2 inhibitor CX-4945, which retains SET in the nucleus, and FTY720, which disrupts the SET-PP2A binding in the cytoplasm, significantly reduces the viability and migration of AML cells. In conclusion, we show that the p38β/CK2/SET axis represents a new potential therapeutic pathway in AML patients with SET-dependent PP2A inactivation.
 

摘要翻译： 

急性髓系白血病（AML）是一种侵袭性血液恶性肿瘤。尽管已有新兴药物问世，但总体预后仍然较差，需要新的治疗方法。PP2A磷酸酶是细胞稳态的关键调节因子，在AML中反复失活。几种PP2A激活药物（如FTY720）的抗癌活性取决于它们与SET癌蛋白的相互作用，SET是一种内源性PP2A抑制剂，在30%的AML病例中过度表达。因此，阐明SET调控机制可能为SET过表达的AML提供新的靶向治疗。在此，我们发现蛋白激酶p38β的上调是AML的常见事件。我们证明p38β通过两种机制增强SET介导的PP2A失活：通过CK2磷酸化促进SET细胞质转运，以及直接结合并稳定SET蛋白。我们在患者原代AML细胞和斑马鱼异种移植模型中证明了这一新调控机制的重要性。因此，将CK2抑制剂CX-4945（使SET保留在细胞核内）与FTY720（破坏细胞质中SET-PP2A结合）联用，可显著降低AML细胞的活力和迁移能力。总之，我们证明p38β/CK2/SET轴代表了SET依赖性PP2A失活的AML患者中一条新的潜在治疗通路。

原文链接：

A new regulatory mechanism of protein phosphatase 2A activity via SET in acute myeloid leukemia