Abstract
Chromosomal translocations and activation of the fibroblast growth factor (FGF) receptor 1 (FGFR1) are a feature of stem cell leukemia-lymphoma syndrome (SCLL), an aggressive malignancy characterized by rapid transformation to acute myeloid leukemia and lymphoblastic lymphoma. It has been suggested that FGFR1 proteins lose their ability to recruit Src kinase, an important mediator of FGFR1 signaling, as a result of the translocations that delete the extended FGFR substrate-2 (FRS2) interacting domain that Src binds. In this study, we report evidence that refutes this hypothesis and reinforces the notion that Src is a critical mediator of signaling from the FGFR1 chimeric fusion genes generated by translocation in SCLL. Src was constitutively active in BaF3 cells expressing exogenous FGFR1 chimeric kinases cultured in vitro as well as in T-cell or B-cell lymphomas they induced in vivo. Residual components of the FRS2-binding site retained in chimeric kinases that were generated by translocation were sufficient to interact with FRS2 and activate Src. The Src kinase inhibitor dasatinib killed transformed BaF3 cells and other established murine leukemia cell lines expressing chimeric FGFR1 kinases, significantly extending the survival of mice with SCLL syndrome. Our results indicated that Src kinase is pathogenically activated in lymphomagenesis induced by FGFR1 fusion genes, implying that Src kinase inhibitors may offer a useful option to treatment of FGFR1-associated myeloproliferative/lymphoma disorders.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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3T3 Cells
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Animals
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Cell Death / genetics
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Cell Growth Processes / genetics
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Cell Line, Tumor
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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Cells, Cultured
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Dasatinib
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Female
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Humans
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Leukemia / enzymology*
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Leukemia / genetics
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Leukemia / metabolism
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Lymphoma, B-Cell / genetics
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Lymphoma, B-Cell / metabolism*
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Lymphoma, T-Cell / genetics
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Lymphoma, T-Cell / metabolism*
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred BALB C
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-bcr / metabolism
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Pyrimidines / pharmacology
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Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors
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Receptor, Fibroblast Growth Factor, Type 1 / genetics
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Receptor, Fibroblast Growth Factor, Type 1 / metabolism*
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Signal Transduction / genetics
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Thiazoles / pharmacology
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Transcription Factors / metabolism
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Translocation, Genetic / genetics
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src-Family Kinases / antagonists & inhibitors
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src-Family Kinases / genetics
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src-Family Kinases / metabolism*
Substances
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DNA-Binding Proteins
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FRS2alpha protein, mouse
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Membrane Proteins
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Oncogene Proteins, Fusion
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Protein Kinase Inhibitors
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Pyrimidines
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Thiazoles
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Transcription Factors
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Zmym2 protein, mouse
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FGFR1 protein, human
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Fgfr1 protein, mouse
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Receptor, Fibroblast Growth Factor, Type 1
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src-Family Kinases
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BCR protein, human
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Bcr protein, mouse
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Proto-Oncogene Proteins c-bcr
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Dasatinib