title: Dasatinib inhibits the growth and survival of neoplastic human eosinophils (EOL-1) through targeting of FIP1L1-PDGFRalpha.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Baumgartner
authors.forename: Karoline V
authors.initials: KV
authors.lastname: Gleixner
authors.forename: Barbara
authors.initials: B
authors.lastname: Peter
authors.forename: Veronika
authors.initials: V
authors.lastname: Ferenc
authors.forename: Alexander
authors.initials: A
authors.lastname: Gruze
authors.forename: Lily L
authors.initials: LL
authors.lastname: Remsing Rix
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.forename: Puchit
authors.initials: P
authors.lastname: Samorapoompichit
authors.forename: Francis Y
authors.initials: FY
authors.lastname: Lee
authors.forename: Winfried F
authors.initials: WF
authors.lastname: Pickl
authors.forename: Harald
authors.initials: H
authors.lastname: Esterbauer
authors.forename: Christian
authors.initials: C
authors.lastname: Sillaber
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects; D000069439:Dasatinib; D004804:Eosinophils / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D017384:Sequence Deletion; D013844:Thiazoles / Q000494:pharmacology*; D013936:Thymidine / Q000378:metabolism; D039221:mRNA Cleavage and Polyadenylation Factors / Q000187:drug effects / Q000502:physiology*
chemical_list: C479818:FIP1L1 protein, human; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D039221:mRNA Cleavage and Polyadenylation Factors; D000069439:Dasatinib; D013936:Thymidine