title: The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management.
abstract: Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL) comprise a spectrum of indolent to aggressive diseases characterized by unexplained, persistent hypereosinophilia. These disorders have eluded a unique molecular explanation, and therapy has primarily been oriented toward palliation of symptoms related to organ involvement. Recent reports indicate that HES and CEL are imatinib-responsive malignancies, with rapid and complete hematologic remissions observed at lower doses than used in chronic myelogenous leukemia (CML). These BCR-ABL-negative cases lack activating mutations or abnormal fusions involving other known target genes of imatinib, implicating a novel tyrosine kinase in their pathogenesis. A bedside-to-benchtop translational research effort led to the identification of a constitutively activated fusion tyrosine kinase on chromosome 4q12, derived from an interstitial deletion, that fuses the platelet-derived growth factor receptor-alpha gene (PDGFRA) to an uncharacterized human gene FIP1-like-1 (FIP1L1). However, not all HES and CEL patients respond to imatinib, suggesting disease heterogeneity. Furthermore, approximately 40% of responding patients lack the FIP1L1-PDGFRA fusion, suggesting genetic heterogeneity. This review examines the current state of knowledge of HES and CEL and the implications of the FIP1L1-PDGFRA discovery on their diagnosis, classification, and management.
authors.affiliation: Division of Hematology, Department of Internal Medicine, Stanford University School of Medicine, Stanford, CA 94305-5821, USA. jason.gotlib@stanford.edu
authors.forename: Jason
authors.initials: J
authors.lastname: Gotlib
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.forename: James M
authors.initials: JM
authors.lastname: Malone
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Schrier
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Steven E
authors.initials: SE
authors.lastname: Coutré
mesh_terms: D000465:Algorithms; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D003582:Cytogenetics; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000145:classification / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D000068877:Imatinib Mesylate; D015514:Oncogene Proteins, Fusion; D010879:Piperazines / Q000627:therapeutic use; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology; D039221:mRNA Cleavage and Polyadenylation Factors / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D011743:Pyrimidines; D039221:mRNA Cleavage and Polyadenylation Factors; D000068877:Imatinib Mesylate; C479819:FIP1L1-PDGFRA fusion protein, human; D011505:Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha