Abstract
The NF1 tumor suppressor gene encodes neurofibromin, a GTPase-activating protein (GAP) for p21ras (Ras). Children with NF1 are predisposed to juvenile myelomonocytic leukemia (JMML). Some heterozygous Nf1 mutant mice develop a similar myeloproliferative disorder (MPD), and adoptive transfer of Nf1-deficient fetal liver cells consistently induces this MPD. Human JMML and murine Nf1-deficient cells are hypersensitive to granulocyte-macrophage colony-stimulating factor (GM-CSF) in methylcellulose cultures. We generated hematopoietic cells deficient in both Nf1 and Gmcsf to test whether GM-CSF is required to drive excessive proliferation of Nf1-/- cells in vivo. Here we show that GM-CSF play a central role in establishing and maintaining the MPD and that recipients engrafted with Nf1-/- Gmcsf-/- hematopoietic cells are hypersensitive to exogenous GM-CSF.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adoptive Transfer
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Animals
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Cell Division
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Child
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Crosses, Genetic
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Female
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Genes, Neurofibromatosis 1*
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Genetic Predisposition to Disease
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Granulocyte-Macrophage Colony-Stimulating Factor / deficiency
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Granulocyte-Macrophage Colony-Stimulating Factor / genetics*
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Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
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Hematopoietic Stem Cell Transplantation*
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Hematopoietic Stem Cells / cytology*
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Hematopoietic Stem Cells / drug effects
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Heterozygote
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Humans
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Leukemia, Myelomonocytic, Chronic / genetics*
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Leukemia, Myelomonocytic, Chronic / pathology
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Liver / embryology
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Inbred Strains
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Mice, Knockout
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Neurofibromin 1
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Proteins / genetics*
Substances
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Neurofibromin 1
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Proteins
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Granulocyte-Macrophage Colony-Stimulating Factor