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Oncogenes, Fusion Genes and Tumor Suppressor Genes

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

Leukemia volume 20, pages 827–832 (2006)Cite this article

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 PDGFRα, 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.

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Acknowledgements

This work was supported by the Leukaemia Research Fund. We are grateful to Drs Valérie Parlier and Dominique Mühlematter of the Unité de Cytogénétique du Cancer, Lausanne for cytogenetic analysis.

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Authors and Affiliations

  1. Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, Wilts, UK

    J Score, C Curtis, K Waghorn, F H Grand & N C P Cross

  2. Human Genetics Division, University of Southampton, Southampton, UK

    J Score, C Curtis, K Waghorn, F H Grand & N C P Cross

  3. Unite d'Hematologie, Consilia SA, Sion, Switzerland

    M Stalder

  4. Unité de Cytogénétique du Cancer, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

    M Jotterand

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  1. J Score
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  2. C Curtis
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Correspondence to N C P Cross.

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Score, J., Curtis, C., Waghorn, K. et al. Identification of a novel imatinib responsive KIF5B-PDGFRA fusion gene following screening for PDGFRA overexpression in patients with hypereosinophilia. Leukemia 20, 827–832 (2006). https://doi.org/10.1038/sj.leu.2404154

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