Reactivating PP2A by FTY720 as a novel therapy for AML with C-KIT tyrosine kinase domain mutation

J Cell Biochem. 2012 Apr;113(4):1314-22. doi: 10.1002/jcb.24003.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Blotting, Western
  • Cell Line, Tumor
  • Enzyme Activation
  • Enzyme Reactivators / therapeutic use*
  • Fingolimod Hydrochloride
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / pathology
  • Mutation*
  • Propylene Glycols / therapeutic use*
  • Protein Phosphatase 2 / metabolism*
  • Proto-Oncogene Proteins c-kit / genetics*
  • Sphingosine / analogs & derivatives*
  • Sphingosine / therapeutic use


  • Enzyme Reactivators
  • Propylene Glycols
  • Proto-Oncogene Proteins c-kit
  • Protein Phosphatase 2
  • Fingolimod Hydrochloride
  • Sphingosine