title: Functional characterization, localization, and inhibitor sensitivity of the TPR-FGFR1 fusion in 8p11 myeloproliferative syndrome.
abstract: Myeloid and lymphoid neoplasms with fibroblast growth factor receptor 1 (FGFR1) abnormalities, also known as 8p11 myeloproliferative syndrome (EMS), represent rare and aggressive disorders, associated with chromosomal aberrations that lead to the fusion of FGFR1 to different partner genes. We report on a third patient with a fusion of the translocated promoter region (TPR) gene, a component of the nuclear pore complex, to FGFR1 due to a novel ins(1;8)(q25;p11p23). The fact that this fusion is a rare but recurrent event in EMS prompted us to examine the localization and transforming potential of the chimeric protein. TPR-FGFR1 localizes in the cytoplasm, although the nuclear pore localization signal of TPR is retained in the fusion protein. Furthermore, TPR-FGFR1 enables cytokine-independent survival, proliferation, and granulocytic differentiation of the interleukin-3 dependent myeloid progenitor cell line 32Dcl3, reflecting the chronic phase of EMS characterized by myeloid hyperplasia. 32Dcl3 cells transformed with the TPR-FGFR1 fusion and treated with increasing concentrations of the tyrosine kinase inhibitors ponatinib (AP24534) and infigratinib (NVP-BGJ398) displayed reduced survival and proliferation with IC50 values of 49.8 and 7.7 nM, respectively. Ponatinib, a multitargeted tyrosine kinase inhibitor, is already shown to be effective against several FGFR1-fusion kinases. Infigratinib, tested only against FGFR1OP2-FGFR1 to date, is also efficient against TPR-FGFR1. Taking its high specificity for FGFRs into account, infigratinib could be beneficial for EMS patients and should be further investigated for the treatment of myeloproliferative neoplasms with FGFR1 abnormalities.
authors.affiliation: Laboratory for Molecular Biology and Tumor Cytogenetics, Department of Internal Medicine I, Hospital Barmherzige Schwestern, Linz, Austria.
authors.forename: Theodora
authors.initials: T
authors.lastname: Malli
authors.affiliation: Department for Internal Medicine I, Hospital Elisabethinen, Linz, Austria.
authors.forename: Veronika
authors.initials: V
authors.lastname: Buxhofer-Ausch
authors.affiliation: Laboratory for Molecular Biology and Tumor Cytogenetics, Department of Internal Medicine I, Hospital Barmherzige Schwestern, Linz, Austria.
authors.forename: Melanie
authors.initials: M
authors.lastname: Rammer
authors.affiliation: Laboratory for Molecular Biology and Tumor Cytogenetics, Department of Internal Medicine I, Hospital Barmherzige Schwestern, Linz, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Erdel
authors.affiliation: Laboratory for Molecular Biology and Tumor Cytogenetics, Department of Internal Medicine I, Hospital Barmherzige Schwestern, Linz, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kranewitter
authors.affiliation: Department of Internal Medicine I, Hospital Barmherzige Schwestern, Linz, Austria.
authors.forename: Holger
authors.initials: H
authors.lastname: Rumpold
authors.affiliation: Laboratory for Molecular Biology and Tumor Cytogenetics, Department of Internal Medicine I, Hospital Barmherzige Schwestern, Linz, Austria.
authors.forename: Renate
authors.initials: R
authors.lastname: Marschon
authors.affiliation: Laboratory for Molecular Biology and Tumor Cytogenetics, Department of Internal Medicine I, Hospital Barmherzige Schwestern, Linz, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Deutschbauer
authors.affiliation: Clinical Institute for Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Simonitsch-Klupp
authors.affiliation: Clinical Departments of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
authors.affiliation: Department of Internal Medicine 2, Donauspital - SMZO, Vienna, Austria.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Muellner-Ammer
authors.affiliation: Department of Internal Medicine 2, Donauspital - SMZO, Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Sebesta
authors.affiliation: Institute for Pathology and Bacteriology, Donauspital - SMZO, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Birkner
authors.affiliation: Laboratory for Molecular Biology and Tumor Cytogenetics, Department of Internal Medicine I, Hospital Barmherzige Schwestern, Linz, Austria.
authors.forename: Gerald
authors.initials: G
authors.lastname: Webersinke
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000235:genetics*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D007093:Imidazoles; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; D010671:Phenylurea Compounds; D011518:Proto-Oncogene Proteins; D011724:Pyridazines; D011743:Pyrimidines; C073597:TPR protein, human; C545373:ponatinib; C568950:infigratinib; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1