Identification of a novel imatinib responsive KIF5B-PDGFRA fusion gene following screening for PDGFRA overexpression in patients with hypereosinophilia.

Abstract

Idiopathic hypereosinophilic syndrome (IHES) is a disease that is difficult to classify, and diagnosis is one of exclusion. The identification of a cytogenetically invisible interstitial deletion resulting in the fusion of FIP1-Like-1 (FIP1L1) to platelet-derived growth factor receptor alpha (PDGFRA) has enabled many IHES cases to be reclassified as chronic eosinophilic leukemia. As it is likely that PDGFRA may fuse to other partner genes, we established a reverse transcriptase-PCR test to detect specific overexpression of the PDGFRA kinase domain as an indicator of the presence of a fusion gene. Overexpression was detected in 12/12 FIP1L1-PDGFRA-positive patients, plus 9/217 (4%) patients with hypereosinophilia who had tested negative for FIP1L1-PDGFRA. One of the positive cases was investigated in detail and found to have a complex karyotype involving chromosomes 3, 4 and 10. Amplification of the genomic breakpoint by bubble PCR revealed a novel fusion between KIF5B at 10p11 and PDGFRA at 4q12. Imatinib, a known inhibitor of PDGFRalpha, produced a complete cytogenetic response and disappearance of the KIF5B-PDGFRA fusion by PCR, from both genomic DNA and mRNA. This study demonstrates the utility of screening for PDGFRA kinase domain overexpression in patients with IHES and has identified a third PDGFRA fusion partner in chronic myeloproliferative disorders.

• Authors: J Score, C Curtis, K Waghorn, M Stalder, M Jotterand, F H Grand, N C P Cross
• Journal: Leukemia (Leukemia) Vol. 20 Issue 5 Pg. 827-32 (May 2006) ISSN: 0887-6924 [Print] England
• PMID: 16498388 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• Piperazines
• Pyrimidines
• RNA, Messenger
• Imatinib Mesylate
• Protein-Tyrosine Kinases
• Receptor, Platelet-Derived Growth Factor alpha

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Benzamides
• Cohort Studies
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Rearrangement
• Genetic Testing
• Humans
• Hypereosinophilic Syndrome (drug therapy, genetics)
• Imatinib Mesylate
• In Situ Hybridization, Fluorescence
• Male
• Middle Aged
• Oncogene Fusion (genetics)
• Piperazines (pharmacology, therapeutic use)
• Protein-Tyrosine Kinases (drug effects, genetics)
• Pyrimidines (pharmacology, therapeutic use)
• RNA, Messenger (drug effects, genetics)
• Receptor, Platelet-Derived Growth Factor alpha (antagonists & inhibitors, genetics)
• Remission Induction
• Reverse Transcriptase Polymerase Chain Reaction (methods)
• Sensitivity and Specificity
• Treatment Outcome