title: The FIP1L1-PDGFRalpha kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia.
abstract: OBJECTIVE
  The idiopathic hypereosinophilic syndrome is a rare hematologic disorder characterized by sustained unexplained eosinophilia with associated end-organ damage and by a striking male predominance. The first insights into the molecular etiology of this heterogeneous disease were obtained from a "bedside-to-bench" approach. Successful empiric treatment of patients with the hypereosinophilic syndrome with the selective tyrosine kinase inhibitor imatinib mesylate (Gleevec, Novartis) ultimately led to the discovery of the FIP1L1-PDGFRalpha fusion kinase in about half of the hypereosinophilic syndrome cases.
  
  
  RESULTS
  The FIP1L1-PDGFRA fusion gene is generated by a cryptic interstitial chromosomal deletion, del(4)(q12q12), which indicates that these cases are clonal hematopoietic malignancies and should be reclassified as chronic eosinophilic leukemias based on current World Health Organization recommendations. In addition, the FIP1L1-PDGFRA fusion gene was also identified in cases with systemic mast cell disease. In vitro and in vivo studies confirmed that FIP1L1-PDGFRalpha is a therapeutic target of imatinib, forming a rational basis for the treatment of FIP1L1-PDGFRA positive chronic eosinophilic leukemia and mastocytosis with imatinib. Similar to BCR-ABL-positive leukemias, resistance to imatinib due to point mutations in the PDGFRalpha kinase domain may develop. We have explored strategies to circumvent resistance to imatinib using alternative tyrosine kinase inhibitors such as PKC412.
  
  
  CONCLUSIONS
  The discovery of the FIP1L1-PDGFRA fusion gene in the hypereosinophilic syndrome is an example of the power of clinical translational research and identifies interstitial chromosomal deletion as a novel mechanism to generate oncogenic tyrosine kinase fusion genes.
authors.affiliation: Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Stover
authors.forename: Iwona
authors.initials: I
authors.lastname: Wlodarska
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017384:Sequence Deletion; D039221:mRNA Cleavage and Polyadenylation Factors / Q000235:genetics* / Q000502:physiology
chemical_list: D015514:Oncogene Proteins, Fusion; D011993:Recombinant Fusion Proteins; D039221:mRNA Cleavage and Polyadenylation Factors; C479819:FIP1L1-PDGFRA fusion protein, human; D020796:Receptor, Platelet-Derived Growth Factor alpha