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

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 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.

Clinical-Grade Peptide-Based Inhibition of CK2 Blocks Viability and Proliferation of T-ALL Cells and Counteracts IL-7 Stimulation and Stromal Support

“…We have also demonstrated that similar mechanisms of CK2-mediated PTEN inactivation exist in B-ALL and CLL and are of relevance for leukemia cell maintenance [12,47,49]. Moreover, CK2 is relevant in biology, and resistance to therapy, of acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) [11,[50][51][52][53]. Thus, there is a clear rationale to explore the use of CK2 inhibitors in the clinical setting in different leukemias, including T-ALL.…”

Diversity and versatility of p38 kinase signalling in health and disease

“…This could be due to the higher p38α expression in most cell types, but might also reflect that p38α can perform particular functions, as suggested by the inability of p38β expressed under control of the p38α endogenous promoter to rescue p38α phenotypes in mice 21 . Nevertheless, experiments with cell cultures have identified some functions that can be mostly performed by p38β 22 . In addition, some cells may rely on p38β as a backup for p38α, as shown by the additional phenotypes observed in mice in which genes encoding both p38α and p38β were knocked out, compared with the single knockouts.…”

Fast, In Vivo Model for Drug-Response Prediction in Patients with B-Cell Precursor Acute Lymphoblastic Leukemia

“…Treatment of engrafted leukemic blasts from patient 4 reflected the poor response during the treatment coarse. Zebrafish have received more attention during the last decade as an embryonic model host for xenografts, with nine publications exploring engraftment of other leukemic blast cell types to date [21,24,25,36,[38][39][40][41]. The ALL-ZeFiX assay both provides proof-of-principle for BCP-ALL exgraftment and extends the clinical utility of drug testing in immunosuppressed zebrafish avatars with quantifiable endpoint analysis and a 5-day assay format.…”