Abstract
The FOP-fibroblast growth factor receptor 1 (FGFR1) fusion protein is expressed as a consequence of a t(6;8) (q27;p12) translocation associated with a stem cell myeloproliferative disorder with lymphoma, myeloid hyperplasia and eosinophilia. In the present report, we show that the fusion of the leucine-rich N-terminal region of FOP to the catalytic domain of FGFR1 results in conversion of murine hematopoietic cell line Ba/F3 to factor-independent cell survival via an antiapoptotic effect. This survival effect is dependent upon the constitutive tyrosine phosphorylation of FOP-FGFR1. Phosphorylation of STAT1 and of STAT3, but not STAT5, is observed in cells expressing FOP-FGFR1. The survival function of FOP-FGFR1 is abrogated by mutation of the phospholipase C gamma binding site. Mitogen-activated protein kinase (MAPK) is also activated in FOP-FGFR1-expressing cells and confers cytokine-independent survival to hematopoietic cells. These results demonstrate that FOP-FGFR1 is capable of protecting cells from apoptosis by using the same effectors as the wild-type FGFR1. Furthermore, we show that FOP-FGFR1 phosphorylates phosphatidylinositol 3 (PI3)-kinase and AKT and that specific inhibitors of PI3-kinase impair its ability to promote cell survival. In addition, FOP-FGFR1-expressing cells show constitutive phosphorylation of the positive regulator of translation p70S6 kinase; this phosphorylation is inhibited by PI3-kinase and mTOR (mammalian target of rapamycin) inhibitors. These results indicate that translation control is important to mediate the cell survival effect induced by FOP-FGFR1. Finally, FOP-FGFR1 protects cells from apoptosis by survival signals including BCL2 overexpression and inactivation of caspase-9 activity. Elucidation of signaling events downstream of FOP-FGFR1 constitutive activation provides insight into the mechanism of leukemogenesis mediated by this oncogenic fusion protein.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Caspase 9
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Caspase Inhibitors
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Cell Line
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Cell Survival / drug effects
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Chromosomes, Human, Pair 6 / genetics
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Chromosomes, Human, Pair 8 / genetics
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DNA-Binding Proteins / metabolism
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Enzyme Inhibitors / pharmacology
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / metabolism*
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Humans
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Isoenzymes / metabolism
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Leucine / genetics*
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Mice
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Mitogen-Activated Protein Kinases / metabolism
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Mutagenesis, Site-Directed
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Myeloproliferative Disorders / genetics
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Myeloproliferative Disorders / metabolism*
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Oncogene Proteins, Fusion / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phospholipase C gamma
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Phosphorylation / drug effects
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Receptor Protein-Tyrosine Kinases / genetics*
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Receptor, Fibroblast Growth Factor, Type 1
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Receptors, Fibroblast Growth Factor / genetics*
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Receptors, Fibroblast Growth Factor / metabolism*
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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Signal Transduction / physiology*
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TOR Serine-Threonine Kinases
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Trans-Activators / metabolism
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Transfection
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Translocation, Genetic / genetics
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Type C Phospholipases / metabolism
Substances
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CEP43 protein, human
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Caspase Inhibitors
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DNA-Binding Proteins
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Enzyme Inhibitors
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FOP-FGFR1 fusion protein, human
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Isoenzymes
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Oncogene Proteins, Fusion
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Fibroblast Growth Factor
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STAT1 Transcription Factor
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STAT1 protein, human
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STAT3 Transcription Factor
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STAT3 protein, human
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Stat1 protein, mouse
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Stat3 protein, mouse
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Trans-Activators
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Protein Kinases
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MTOR protein, human
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mTOR protein, mouse
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FGFR1 protein, human
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Fgfr1 protein, mouse
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Receptor Protein-Tyrosine Kinases
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Receptor, Fibroblast Growth Factor, Type 1
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Mitogen-Activated Protein Kinases
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Type C Phospholipases
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Phospholipase C gamma
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CASP9 protein, human
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Casp9 protein, mouse
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Caspase 9
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Leucine