title: A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome.
abstract: BACKGROUND
  Idiopathic hypereosinophilic syndrome involves a prolonged state of eosinophilia associated with organ dysfunction. It is of unknown cause. Recent reports of responses to imatinib in patients with the syndrome suggested that an activated kinase such as ABL, platelet-derived growth factor receptor (PDGFR), or KIT, all of which are inhibited by imatinib, might be the cause.
  
  
  METHODS
  We treated 11 patients with the hypereosinophilic syndrome with imatinib and identified the molecular basis for the response.
  
  
  RESULTS
  Nine of the 11 patients treated with imatinib had responses lasting more than three months in which the eosinophil count returned to normal. One such patient had a complex chromosomal abnormality, leading to the identification of a fusion of the Fip1-like 1 (FIP1L1) gene to the PDGFRalpha (PDGFRA) gene generated by an interstitial deletion on chromosome 4q12. FIP1L1-PDGFRalpha is a constitutively activated tyrosine kinase that transforms hematopoietic cells and is inhibited by imatinib (50 percent inhibitory concentration, 3.2 nM). The FIP1L1-PDGFRA fusion gene was subsequently detected in 9 of 16 patients with the syndrome and in 5 of the 9 patients with responses to imatinib that lasted more than three months. Relapse in one patient correlated with the appearance of a T674I mutation in PDGFRA that confers resistance to imatinib.
  
  
  CONCLUSIONS
  The hypereosinophilic syndrome may result from a novel fusion tyrosine kinase - FIP1L1-PDGFRalpha - that is a consequence of an interstitial chromosomal deletion. The acquisition of a T674I resistance mutation at the time of relapse demonstrates that FIP1L1-PDGFRalpha is the target of imatinib. Our data indicate that the deletion of genetic material may result in gain-of-function fusion proteins.
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, USA
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: DeAngelo
authors.forename: Jason
authors.initials: J
authors.lastname: Gotlib
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Stover
authors.forename: Robert D
authors.initials: RD
authors.lastname: Legare
authors.forename: Jorges
authors.initials: J
authors.lastname: Cortes
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kutok
authors.forename: Jennifer
authors.initials: J
authors.lastname: Clark
authors.forename: Ilene
authors.initials: I
authors.lastname: Galinsky
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
authors.forename: Ayalew
authors.initials: A
authors.lastname: Tefferi
authors.forename: James
authors.initials: J
authors.lastname: Malone
authors.forename: Rafeul
authors.initials: R
authors.lastname: Alam
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Schrier
authors.forename: Janet
authors.initials: J
authors.lastname: Schmid
authors.forename: Michal
authors.initials: M
authors.lastname: Rose
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
authors.forename: Gregor
authors.initials: G
authors.lastname: Verhoef
authors.forename: Marc
authors.initials: M
authors.lastname: Boogaerts
authors.forename: Iwona
authors.initials: I
authors.lastname: Wlodarska
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: Steven E
authors.initials: SE
authors.lastname: Coutre
authors.forename: Richard
authors.initials: R
authors.lastname: Stone
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
mesh_terms: D000328:Adult; D001483:Base Sequence; D001549:Benzamides; D002872:Chromosome Deletion; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000188:drug therapy / Q000235:genetics*; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010879:Piperazines / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use*; D011995:Recombination, Genetic; D012074:Remission Induction / Q000379:methods
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases