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)

Bartosz Wasag; Els Lierman; Peter Meeus; Jan Cools; Peter Vandenberghe

doi:10.3324/haematol.2010.036558

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)

Haematologica. 2011 Jun;96(6):922-6. doi: 10.3324/haematol.2010.036558. Epub 2011 Feb 17.

Authors

Bartosz Wasag¹, Els Lierman, Peter Meeus, Jan Cools, Peter Vandenberghe

Affiliation

¹ Center for Human Genetics, K.U.Leuven, O&N1 Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.

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.

Publication types

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

MeSH terms

Adult
Base Sequence
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Transformation, Neoplastic
Chromosomes, Human, Pair 7 / genetics*
Chromosomes, Human, Pair 8 / genetics*
Cytogenetics
Female
Homeodomain Proteins* / genetics
Homeodomain Proteins* / metabolism
Humans
Nuclear Proteins* / genetics
Nuclear Proteins* / metabolism
Oncogene Proteins, Fusion / metabolism
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use*
Receptor, Fibroblast Growth Factor, Type 1* / genetics
Receptor, Fibroblast Growth Factor, Type 1* / metabolism
Repressor Proteins* / genetics
Repressor Proteins* / metabolism
Transcription Factors
Translocation, Genetic / genetics*

Substances

CUX1 protein, human
Homeodomain Proteins
Nuclear Proteins
Oncogene Proteins, Fusion
Protein Kinase Inhibitors
Repressor Proteins
Transcription Factors
Receptor, Fibroblast Growth Factor, Type 1