A new regulatory mechanism of protein phosphatase 2A activity via SET in acute myeloid leukemia
Keywords: 
Activation
Kinase
Cancer
Midostaurin
Inhibition
Complex
Alpha
Ck2
Phosphorylation
Overexpression
Issue Date: 
2020
ISSN: 
2044-5385
Editorial note: 
This article is licensed under a Creative Commons Attribution 4.0 International License
Note: 
This article is licensed under a Creative Commons Attribution 4.0 International License
Citation: 
Odero-de Dios, M. (María Dolores); Nebreda, A. R.; Cayuela, M. L.; et al. "A new regulatory mechanism of protein phosphatase 2A activity via SET in acute myeloid leukemia". Blood Cancer Journal. 10 (1), 2020,
Abstract
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 p38 beta is a common event in AML. We provide evidence that p38 beta 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 p38 beta/CK2/SET axis represents a new potential therapeutic pathway in AML patients with SET-dependent PP2A inactivation.

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