title: 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.
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury and Human Genetics Division, University of Southampton, Southampton, United Kingdom.
authors.forename: Francis H
authors.initials: FH
authors.lastname: Grand
authors.forename: Sonja
authors.initials: S
authors.lastname: Burgstaller
authors.forename: Thomas
authors.initials: T
authors.lastname: Kühr
authors.forename: E Joanna
authors.initials: EJ
authors.lastname: Baxter
authors.forename: Gerald
authors.initials: G
authors.lastname: Webersinke
authors.forename: Josef
authors.initials: J
authors.lastname: Thaler
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Chase
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D001549:Benzamides; D002884:Chromosomes, Human, Pair 15; D002895:Chromosomes, Human, Pair 5; D004802:Eosinophilia / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics*; D010879:Piperazines / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014178:Translocation, Genetic; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D047908:Intracellular Signaling Peptides and Proteins; D015514:Oncogene Proteins, Fusion; D010750:Phosphoproteins; D010879:Piperazines; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D000068877:Imatinib Mesylate