Reactivating PP2A by FTY720 as a Novel therapy for AML with C-KIT tyrosine kinase domain mutation
✍ Scribed by Yan Yang; Qing Huang; Yanjun Lu; Xiaoqing Li; Shiang Huang
- Publisher
- John Wiley and Sons
- Year
- 2012
- Tongue
- English
- Weight
- 373 KB
- Volume
- 113
- Category
- Article
- ISSN
- 0730-2312
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✦ Synopsis
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. J. Cell. Biochem. 113: 1314–1322, 2012. © 2011 Wiley Periodicals, Inc.