Imatinib mesylate is effective in the treatment of hematologic malignancies that are characterized by either abl-or PDGFR␤-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␣ (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 ␣ (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. IntroductionImatinib mesylate (Gleevec), a small-molecule tyrosine kinase inhibitor from the 2-phenylaminopyrimidine class of compounds, has shown activity in the treatment of malignancies that are associated with the constitutive activation of a specific subgroup of tyrosine kinases. Imatinib mesylate-sensitive malignancies include chronic myeloid leukemia (CML) 1,2 and gastrointestinal stromal tumors (GISTs) 3,4 that are associated with the activation of bcr-abl and c-kit tyrosine kinases, respectively. More recently, imatinib mesylate has proven effective in the treatment of hypereosinophilic syndrome (HES) 5-10 and chronic myeloproliferative disorders that are associated with rearrangement of the PDGFR␤ gene. 11 Both types of disorders are characterized by prominent peripheral blood and bone marrow eosinophilia, with symptoms and signs of organ infiltration by eosinophils. In a recent study, a novel tyrosine kinase, generated from fusion of the Fip1-like 1 (FIP1L1) gene to the PDGFRA gene, was identified in 9 of 16 patients (56%) with HES. 10 This fusion results from an approximately 800-kb interstitial chromosomal deletion that includes the cysteine-rich hydrophobic domain 2 (CHIC2) locus. FIP1L1-platelet-derived growth factor receptor ␣ (PDGFRA) is a constitutively activated tyrosine kinase that transforms hematopoietic cells and is a therapeutic target for imatinib mesylate in a subset of HES patients.Mast cell disease (MCD) is a clinically heterogenous disorder wherein accumulation...

A novel oncogenic mutation (FIP1L1-PDGFRA), which results in a constitutively activated platelet-derived growth factor receptor-␣ (PDGFRA), has been invariably associated with a primary eosinophilic disorder. The current study examines both the prevalence and the associated clinicopathologic features of this mutation in a cohort of 89 adult patients presenting with an absolute eosinophil count (AEC) of higher than 1.5 ؋ 10 9 /L. A fluorescence in situ hybridization (FISH)-based strategy was used to detect FIP1L1-PDGFRA in bone marrow cells.