title: The kinase inhibitor TKI258 is active against the novel CUX1-FGFR1 fusion detected in a patient with T-lymphoblastic leukemia/lymphoma and t(7;8)(q22;p11).
abstract: We report a patient with T-lymphoblastic leukemia/lymphoma and a t(7;8)(q22;p11). CUX1 was identified as the fusion partner of FGFR1 by fluorescence in situ hybridization and 5' RACE-PCR. We further investigated this novel FGFR1 fusion using the interleukin-3 (IL-3) dependent Ba/F3 cell line and demonstrated IL-3 independent cell growth of CUX1-FGFR1 expressing cells. TKI258 and PKC412 potently inhibited proliferation of CUX1-FGFR1 transformed Ba/F3 cells. This growth inhibition was shown to be mediated by inhibition of CUX1-FGFR1 kinase activity for TKI258 but not PKC412. In summary, we identified a novel CUX1-FGFR1 fusion oncogene in a patient with the 8p11 myeloproliferative syndrome and demonstrated its transforming potential in the Ba/F3 cell line. Our in vitro data support the further investigation of TKI258 for the treatment of constitutively active FGFR1 fusion proteins.
authors.affiliation: Center for Human Genetics, K.U.Leuven, O&N1 Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Wasag
authors.forename: Els
authors.initials: E
authors.lastname: Lierman
authors.forename: Peter
authors.initials: P
authors.lastname: Meeus
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
mesh_terms: D000328:Adult; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D003582:Cytogenetics; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: C080632:CUX1 protein, human; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D012097:Repressor Proteins; D014157:Transcription Factors; D051496:Receptor, Fibroblast Growth Factor, Type 1