p53-Binding protein 1 is fused to the platelet-derived growth factor receptor beta in a patient with a t(5;15)(q33;q22) and an imatinib-responsive eosinophilic myeloproliferative disorder

Cancer Res. 2004 Oct 15;64(20):7216-9. doi: 10.1158/0008-5472.CAN-04-2005.

Abstract

We describe the fusion of TP53BP1 to PDGFRB in a patient with a chronic myeloid leukemia-like disorder associated with eosinophilia and a t(5;15)(q33;q22). TP53BP1 encodes 53BP1, a p53-binding protein that plays a role in cellular responses to DNA damage. The 53BP1-PDGFRbeta fusion protein is predicted to retain the kinetochore-binding domain of 53BP1 fused to the transmembrane and intracellular tyrosine kinase domain of PDGFRbeta. The presence of the fusion was confirmed by two-color fluorescence in situ hybridization, reverse transcription-PCR, and by characterizing the genomic breakpoints. The reciprocal fusion, which would contain the p53-binding 53BP1 BRCA1 COOH-terminal domains, was not detectable by fluorescence in situ hybridization or nested PCR. Imatinib, a known inhibitor of PDGFRbeta, blocked the growth of patient colony-forming unit, granulocyte-macrophage in vitro and produced a clinically significant response before relapse and subsequent death with imatinib-resistant disease. We conclude that TP53BP1-PDGFRB is a novel imatinib target in atypical chronic myeloid leukemia.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Amino Acid Sequence
  • Antineoplastic Agents / pharmacology*
  • Base Sequence
  • Benzamides
  • Chromosomes, Human, Pair 15
  • Chromosomes, Human, Pair 5
  • Eosinophilia / drug therapy
  • Eosinophilia / genetics*
  • Humans
  • Imatinib Mesylate
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Male
  • Molecular Sequence Data
  • Myeloproliferative Disorders / drug therapy
  • Myeloproliferative Disorders / genetics*
  • Oncogene Proteins, Fusion / genetics*
  • Phosphoproteins / genetics*
  • Piperazines / pharmacology*
  • Proto-Oncogene Proteins c-sis / genetics*
  • Pyrimidines / pharmacology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Translocation, Genetic
  • Tumor Suppressor p53-Binding Protein 1

Substances

  • Antineoplastic Agents
  • Benzamides
  • Intracellular Signaling Peptides and Proteins
  • Oncogene Proteins, Fusion
  • Phosphoproteins
  • Piperazines
  • Proto-Oncogene Proteins c-sis
  • Pyrimidines
  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1
  • Imatinib Mesylate