title: Reactivating PP2A by FTY720 as a novel therapy for AML with C-KIT tyrosine kinase domain mutation.
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.
authors: Center for Stem Cell Research and Application, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors: Yan
authors: Y
authors: Yang
authors: Qing
authors: Q
authors: Huang
authors: Yanjun
authors: Y
authors: Lu
authors: Xiaoqing
authors: X
authors: Li
authors: Shiang
authors: S
authors: Huang
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004793:Enzyme Reactivators / Q000627:therapeutic use*; D000068876:Fingolimod Hydrochloride; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D009154:Mutation; D011409:Propylene Glycols / Q000627:therapeutic use*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D004793:Enzyme Reactivators; D011409:Propylene Glycols; D019009:Proto-Oncogene Proteins c-kit; D054648:Protein Phosphatase 2; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine