Abstract
Despite their known transforming properties, the effects of leukemogenic FLT3-ITD mutations on hematopoietic stem and multipotent progenitor cells and on hematopoietic differentiation are not well understood. We report a mouse model harboring an ITD in the murine Flt3 locus that develops myeloproliferative disease resembling CMML and further identified FLT3-ITD mutations in a subset of human CMML. These findings correlated with an increase in number, cell cycling, and survival of multipotent stem and progenitor cells in an ITD dose-dependent manner in animals that exhibited alterations within their myeloid progenitor compartments and a block in normal B cell development. This model provides insights into the consequences of constitutive signaling by an oncogenic tyrosine kinase on hematopoietic progenitor quiescence, function, and cell fate.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Differentiation
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Cell Proliferation*
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Cell Survival
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Cells, Cultured
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Exons
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Gene Expression Regulation, Neoplastic
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Genotype
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Hematopoietic Stem Cells / metabolism*
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Hematopoietic Stem Cells / pathology
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Humans
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Kaplan-Meier Estimate
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Leukemia, Experimental / metabolism
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Leukemia, Experimental / pathology
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Leukemia, Myelomonocytic, Chronic / genetics
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Leukemia, Myelomonocytic, Chronic / metabolism*
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Leukemia, Myelomonocytic, Chronic / mortality
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Leukemia, Myelomonocytic, Chronic / pathology
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Transgenic
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Multipotent Stem Cells / metabolism*
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Multipotent Stem Cells / pathology
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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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Phenotype
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Signal Transduction
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fms-Like Tyrosine Kinase 3 / genetics
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fms-Like Tyrosine Kinase 3 / metabolism*
Substances
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FLT3 protein, human
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Flt3 protein, mouse
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fms-Like Tyrosine Kinase 3