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Reactivating PP2A by FTY720 as a novel therapy for AML with C-KIT tyrosine kinase domain mutation
Yan Yang1, Qing Huang, Yanjun Lu
1Center for Stem Cell Research and Application, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Abstract:
The tyrosine kinase domain (TKD) mutations of receptor tyrosine kinase C-KIT are associated with a poor prognosis in acute myeloid leukemia (AML). However, the underlying mechanisms are not fully understood. We found the activity of protein phosphatase 2A (PP2A), a human tumor suppressor whose dysfunction contributes to malignant cell behavior, was significantly decreased in AML subgroups harboring C-KIT/D816V and AML cell line Kasumi-1 bearing C-KIT/N822K mutation. Primary AML cells and various AML cell lines were treated with PP2A activator FTY720. FTY720 showed a toxic effect in all leukemic cells, especially for cells harboring C-KIT/TKD mutation. Furthermore, FTY720-induced toxicity in AML leukemic cells was mediated by restoration of PP2A activity, via down-regulation of PP2A inhibitor SET, dephosporylation of PP2A-C(TYR307), and up-regulation of relevant PP2A subunit A and B55α. Our research indicates that the decreased PP2A activity in AML harboring C-KIT/TKD mutation may make the restoration of PP2A activity a novel therapy for AML patients with C-KIT/TKD mutation.
Insights
Decreased protein phosphatase 2A (PP2A) activity is linked to poor prognosis in acute myeloid leukemia (AML) with C-KIT tyrosine kinase domain (TKD) mutations. Activating PP2A with FTY720 showed therapeutic potential for these AML patients.
Area of Science:
- Oncology
- Molecular Biology
- Hematology
Background:
- Tyrosine kinase domain (TKD) mutations in receptor tyrosine kinase C-KIT are associated with poor prognosis in acute myeloid leukemia (AML).
- The precise mechanisms linking C-KIT mutations to AML progression remain incompletely understood.
- Protein phosphatase 2A (PP2A), a tumor suppressor, is often dysfunctional in cancers, including AML.
Purpose of the Study:
- To investigate the role of PP2A activity in AML with C-KIT/TKD mutations.
- To evaluate the therapeutic potential of PP2A activation in AML harboring C-KIT/TKD mutations.
Main Methods:
- Assessed PP2A activity in AML subgroups with C-KIT/D816V and C-KIT/N822K mutations.
- Treated primary AML cells and cell lines with the PP2A activator FTY720.
- Analyzed the molecular mechanisms of FTY720-induced toxicity, including PP2A inhibitor SET levels and PP2A subunit expression.
Main Results:
- PP2A activity was significantly decreased in AML subgroups with C-KIT/TKD mutations.
- FTY720 demonstrated significant toxicity in all tested leukemic cells, particularly those with C-KIT/TKD mutations.
- FTY720-induced toxicity was mediated by restored PP2A activity, evidenced by decreased SET, dephosphorylation of PP2A-C(TYR307), and increased PP2A subunit A and B55α expression.
Conclusions:
- Reduced PP2A activity is a key feature of AML with C-KIT/TKD mutations.
- Restoring PP2A activity via FTY720 represents a potential novel therapeutic strategy for AML patients with C-KIT/TKD mutations.
