Abstract
Constitutive activation of aberrant fibroblast growth factor receptor 1 (FGFR1) kinase as a consequence of gene fusion such as FOP-FGFR1 associated with t(6; 8)(q27;p11-12) translocation, is the hallmark of an atypical aggressive stem cell myeloproliferative disorder (MPD) in humans. In this study, we show that expression of FOP-FGFR1 in primary bone marrow cells induced by retroviral transduction generates a MPD in mice. Constitutive FOP-FGFR1 kinase activity was both essential and sufficient to cause a chronic myeloproliferative syndrome in the murine bone marrow transplantation model. In contrast to the human disorder, lymphoproliferation and progression to acute phase were not observed. Lymphoid symptoms, however, appeared when onset of the disease was delayed as the result of mutation of FOP-FGFR1 at tyrosine 511, the phospholipase C gamma (PLCgamma) binding site.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Marrow Transplantation
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Cell Transformation, Neoplastic / genetics
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Female
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Humans
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In Vitro Techniques
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Male
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Mice
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Mice, Inbred C57BL
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Mutation
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Myeloproliferative Disorders / genetics*
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Myeloproliferative Disorders / metabolism*
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Myeloproliferative Disorders / pathology
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Oncogene Proteins, Fusion / genetics*
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Oncogene Proteins, Fusion / metabolism*
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Receptor Protein-Tyrosine Kinases / genetics*
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Receptor Protein-Tyrosine Kinases / metabolism*
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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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Transduction, Genetic
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Translocation, Genetic
Substances
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FOP-FGFR1 fusion protein, human
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Oncogene Proteins, Fusion
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Receptors, Fibroblast Growth Factor
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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