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␤-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...

Systemic mastocytosis in adults: 2015 update on diagnosis, risk stratification, and management

“…In the presence of blood eosinophilia, screening for FIP1L1-PDGFRA, using either FISH or RT-PCR, is warranted [16]. In contrast, conventional cytogenetics analysis generally permits identification of cases of BMM associated with a PDGFRB rearrangement (i.e., chromosomal translocations involving 5q31-32) [18].…”

Five years since the discovery of FIP1L1–PDGFRA: what we have learned about the fusion and other molecularly defined eosinophilias

“…2,8,13 Shortly, after its initial discovery in HES/CEL patients, the Mayo group linked the FIP1L1-PDGFRA fusion to pathologically confirmed cases of systemic mastocytosis with eosinophilia (SM-eo). 69 Histopathologically, the bone marrows of patients with FIP1L1-PDGFRA-positive SM-Eo exhibit less dense clusters of mast cells by tryptase immunostaining than are typically seen in SM, particularly cases with the common D816V KIT mutation. 11 However, in some cases of CEL with increased bone marrow mast cells, the mast cells may exhibit spindle-shaped morphology, form multifocal clusters and aberrant surface expression of CD25, major and minor criteria, which establish the basis for a WHO diagnosis of SM.…”

“…As the CHIC2 gene is located in this region, this FISH test is sometimes referred to as 'FISH to detect the CHIC2 deletion.' 69 A more sensitive way to detect the presence of the FIP1L1-PDGFRA fusion gene in the blood of eosinophilia patients is the use of (nested) reverse transcription (RT)-PCR. Despite the fact that the break points in the FIP1L1 gene can be very different from patient to patient, a single primer combination is sufficient to detect the fusion transcript from most patients.…”

Detection and molecular monitoring of FIP1L1-PDGFRA-positive disease by analysis of patient-specific genomic DNA fusion junctions

“…13 Unambiguous detection of FIP1L1-PDGFRA, however, is complicated by several factors. Fluorescence in situ hybridization (FISH) to detect heterozygous deletion of CHIC2, a surrogate marker for FIP1L1-PDGFRA, can be difficult because of the inherent background fluorescence of eosinophils 9 and the variability in the proportion of cells involved in the malignant clone, 14,15 which is often low and may overlap with the intrinsic background false-positive rate of this technique. Reverse transcriptase polymerase chain reaction (RT-PCR) is complicated by the considerable diversity of break points within FIP1L1, the complex alternative splicing of FIP1L1 and the variable use of cryptic splice sites in the fusion gene.…”