Dasatinib inhibits the growth and survival of neoplastic human eosinophils (EOL-1) through targeting of FIP1L1-PDGFRalpha

Exp Hematol. 2008 Oct;36(10):1244-53. doi: 10.1016/j.exphem.2008.04.017. Epub 2008 Jul 10.


Objective: Chronic eosinophilic leukemia (CEL) is a myeloproliferative disorder characterized by molecular and/or cytogenetic evidence of clonality of eosinophils, marked eosinophilia, and organ damage. In many patients, the transforming mutation FIP1L1-PDGFRalpha and the related CHIC2 deletion are found. The respective oncoprotein, FIP1L1-PDGFRalpha, is considered to play a major role in malignant cell growth in CEL. The tyrosine kinase (TK) inhibitor imatinib (STI571) has been described to counteract the TK activity of FIP1L1-PDGFRalpha in most patients. However, not all patients with CEL show a response to imatinib. Therefore, several attempts have been made to identify other TK inhibitors that counteract growth of neoplastic eosinophils.

Materials and methods: We provide evidence that dasatinib, a multi-targeted kinase inhibitor, blocks the growth and survival of EOL-1, an eosinophil leukemia cell line carrying FIP1L1-PDGFRalpha.

Results: The effects of dasatinib on proliferation of EOL-1 cells were dose-dependent, with an IC50 of 0.5 to 1 nM, which was found to be in the same range when compared to IC50 values produced with imatinib. Dasatinib was also found to induce apoptosis in EOL-1 cells in a dose-dependent manner (IC50: 1-10 nM). The apoptosis-inducing effects of dasatinib on EOL-1 cells were demonstrable by light microscopy, flow cytometry, and in a TUNEL assay. In Western blot experiments, dasatinib completely blocked the phosphorylation of FIP1L1-PDGFRalpha in EOL-1 cells.

Conclusions: Dasatinib inhibits the growth of leukemic eosinophils through targeting of the disease-related oncoprotein FIP1L1-PDGFRalpha. Based on this observation, dasatinib may be considered as a new interesting treatment option for patients with CEL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Cell Division / drug effects*
  • Cell Line, Tumor
  • Cell Survival / drug effects*
  • DNA Replication / drug effects
  • Dasatinib
  • Eosinophils / drug effects
  • Eosinophils / enzymology
  • Eosinophils / physiology*
  • Flow Cytometry
  • Humans
  • Hypereosinophilic Syndrome / drug therapy*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / pharmacology*
  • Sequence Deletion
  • Thiazoles / pharmacology*
  • Thymidine / metabolism
  • mRNA Cleavage and Polyadenylation Factors / drug effects
  • mRNA Cleavage and Polyadenylation Factors / physiology*


  • FIP1L1 protein, human
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Thiazoles
  • mRNA Cleavage and Polyadenylation Factors
  • Dasatinib
  • Thymidine