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: Theodora Malli, Veronika Buxhofer-Ausch, Melanie Rammer, Martin Erdel, Wolfgang Kranewitter, Holger Rumpold, Renate Marschon, Sabine Deutschbauer, Ingrid Simonitsch-Klupp, Peter Valent, Kirsten Muellner-Ammer, Christian Sebesta, Thomas Birkner, Gerald Webersinke
• Journal: Genes, chromosomes & cancer (Genes Chromosomes Cancer) Vol. 55 Issue 1 Pg. 60-8 (Jan 2016) ISSN: 1098-2264 [Electronic] United States
• PMID: 26391436 (Publication Type: Case Reports, Journal Article)
• Copyright: © 2015 Wiley Periodicals, Inc.

Chemical References

• Imidazoles
• Nuclear Pore Complex Proteins
• Oncogene Proteins, Fusion
• Phenylurea Compounds
• Proto-Oncogene Proteins
• Pyridazines
• Pyrimidines
• TPR protein, human
• ponatinib
• infigratinib
• FGFR1 protein, human
• Receptor, Fibroblast Growth Factor, Type 1

Topics

• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Chromosomes, Human, Pair 8 (genetics)
• Cytoplasm (metabolism)
• Humans
• Imidazoles (pharmacology, therapeutic use)
• Male
• Middle Aged
• Mutagenesis, Insertional
• Myeloproliferative Disorders (drug therapy, genetics)
• Nuclear Pore Complex Proteins (genetics, metabolism)
• Oncogene Proteins, Fusion (genetics, metabolism)
• Phenylurea Compounds (pharmacology, therapeutic use)
• Proto-Oncogene Proteins (genetics, metabolism)
• Pyridazines (pharmacology, therapeutic use)
• Pyrimidines (pharmacology, therapeutic use)
• Receptor, Fibroblast Growth Factor, Type 1 (genetics, metabolism)