Premium
Reactivating PP2A by FTY720 as a Novel therapy for AML with C‐KIT tyrosine kinase domain mutation
Author(s) -
Yang Yan,
Huang Qing,
Lu Yanjun,
Li Xiaoqing,
Huang Shiang
Publication year - 2012
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.24003
Subject(s) - protein phosphatase 2 , myeloid leukemia , cancer research , tyrosine kinase , ptpn11 , mutation , cell culture , phosphatase , biology , signal transduction , enzyme , gene , biochemistry , genetics , kras
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. J. Cell. Biochem. 113: 1314–1322, 2012. © 2011 Wiley Periodicals, Inc.