CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy.
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.
Pardanani
Animesh
A
Division of Hematology and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Ketterling
Rhett P
RP
Brockman
Stephanie R
SR
Flynn
Heather C
HC
Paternoster
Sarah F
SF
Shearer
Brandon M
BM
Reeder
Terra L
TL
Li
Chin-Yang
CY
Cross
Nicholas C P
NC
Cools
Jan
J
Gilliland
D Gary
DG
Dewald
Gordon W
GW
Tefferi
Ayalew
A
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*
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