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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.

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.
AuthorsFrancis H Grand, Sonja Burgstaller, Thomas Kühr, E Joanna Baxter, Gerald Webersinke, Josef Thaler, Andrew J Chase, Nicholas C P Cross
JournalCancer research (Cancer Res) Vol. 64 Issue 20 Pg. 7216-9 (Oct 15 2004) ISSN: 0008-5472 [Print] United States
PMID15492236 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 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
Topics
  • Aged
  • Amino Acid Sequence
  • Antineoplastic Agents (pharmacology)
  • Base Sequence
  • Benzamides
  • Chromosomes, Human, Pair 15
  • Chromosomes, Human, Pair 5
  • Eosinophilia (drug therapy, genetics)
  • Humans
  • Imatinib Mesylate
  • Intracellular Signaling Peptides and Proteins (genetics)
  • Male
  • Molecular Sequence Data
  • Myeloproliferative Disorders (drug therapy, 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

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