title: CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy.
abstract: Imatinib mesylate is effective in the treatment of hematologic malignancies that are characterized by either abl- or PDGFR beta- activating mutations. The drug is also active in a subset of patients with eosinophilic disorders and systemic mast cell disease (SMCD). Recently, a novel tyrosine kinase that is generated from fusion of the Fip1-like 1 (FIP1L1) and PDGFR alpha (PDGFRA) genes has been identified as a therapeutic target for imatinib mesylate in hypereosinophilic syndrome (HES). We used fluorescence in situ hybridization (FISH) to detect deletion of the CHIC2 locus at 4q12 as a surrogate for the FIP1L1-PDGFRA fusion. CHIC2 deletion was observed in bone marrow cells for 3 of 5 patients with SMCD associated with eosinophilia. Deletion of this locus and expression of the FIP1L1-platelet-derived growth factor receptor alpha (PDGFRA) fusion was also documented in enriched eosinophils, neutrophils, or mononuclear cells by both FISH and reverse transcriptase-polymerase chain reaction (RT-PCR) for one patient. While all 3 patients with the FIP1L1-PDGFRA rearrangement achieved a sustained complete response with imatinib mesylate therapy, the other two, both carrying the c-kit Asp816 to Val (Asp816Val) mutation, did not. These observations suggest that the FIP1L1-PDGFRA rearrangement occurs in an early hematopoietic progenitor and suggests that the molecular pathogenesis for a subset of SMCD patients is similar to that of HES. Screening for the FIP1L1-PDGFRA rearrangement and Asp816Val mutation will advance rational therapy decisions in SMCD.
authors.affiliation: Division of Hematology and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Animesh
authors.initials: A
authors.lastname: Pardanani
authors.forename: Rhett P
authors.initials: RP
authors.lastname: Ketterling
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Brockman
authors.forename: Heather C
authors.initials: HC
authors.lastname: Flynn
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Paternoster
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Shearer
authors.forename: Terra L
authors.initials: TL
authors.lastname: Reeder
authors.forename: Chin-Yang
authors.initials: CY
authors.lastname: Li
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Dewald
authors.forename: Ayalew
authors.initials: A
authors.lastname: Tefferi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides; D004802:Eosinophilia / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D015321:Gene Rearrangement; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000235:genetics; D000068877:Imatinib Mesylate; D017404:In Situ Hybridization, Fluorescence; D034721:Mastocytosis, Systemic / Q000150:complications / Q000188:drug therapy / Q000235:genetics*; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion; D010879:Piperazines / Q000008:administration & dosage* / Q000627:therapeutic use; D011237:Predictive Value of Tests; D011446:Prospective Studies; D011743:Pyrimidines / Q000008:administration & dosage* / Q000627:therapeutic use; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D016896:Treatment Outcome; D039221:mRNA Cleavage and Polyadenylation Factors / Q000235:genetics*
chemical_list: D001549:Benzamides; C479818:FIP1L1 protein, human; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D011743:Pyrimidines; D039221:mRNA Cleavage and Polyadenylation Factors; D000068877:Imatinib Mesylate; C479819:FIP1L1-PDGFRA fusion protein, human; D020796:Receptor, Platelet-Derived Growth Factor alpha