Abstract
The development of molecularly targeted treatments of adult leukemias warrants investigation of these targets in similar pediatric leukemias. The NF1 tumor suppressor gene, which encodes a GTPase activating protein for p21(ras), is frequently inactivated in juvenile myelomonocytic leukemia (JMML). Other patients with JMML acquire activating RAS gene mutations. Recipient mice reconstituted with Nf1-/- fetal hematopoietic cells develop a myeloproliferative disease (MPD) that models the human disease. JMML arises from clonal expansion of a hematopoietic stem cell, and JMML cells and murine Nf1-/- hematopoietic cells are hypersensitive to granulocyte macrophage-colony stimulating factor and KitL, the ligand for c-kit. We generated embryos doubly mutant for the Wv allele of c-kit and Nf1 to ask if reduction of c-kit activity would delay or prevent the development of MPD. Despite a reduction in c-kit activity to approximately 10% of wild-type levels, Nf1-/-;Wv/Wv cells induced MPD in recipient mice.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alleles
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Animals
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Cell Transformation, Neoplastic / genetics*
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Colony-Forming Units Assay
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Crosses, Genetic
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Disease Models, Animal*
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Gene Targeting
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Genes, Neurofibromatosis 1*
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Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
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Hematopoietic Stem Cell Transplantation / adverse effects*
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Interleukin-1 / pharmacology
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Interleukin-3 / pharmacology
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Leukemia, Myelomonocytic, Acute / genetics*
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Liver / cytology
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Liver / embryology
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Macrophage Colony-Stimulating Factor / pharmacology
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Mice
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Mice, Inbred C57BL
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Mice, Mutant Strains
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Myeloproliferative Disorders / etiology*
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Neurofibromin 1 / deficiency*
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Proto-Oncogene Proteins c-kit / genetics
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Proto-Oncogene Proteins c-kit / physiology*
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Radiation Chimera
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Recombinant Proteins / pharmacology
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Stem Cell Factor / pharmacology
Substances
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Interleukin-1
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Interleukin-3
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Neurofibromin 1
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Recombinant Proteins
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Stem Cell Factor
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Macrophage Colony-Stimulating Factor
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Granulocyte-Macrophage Colony-Stimulating Factor
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Proto-Oncogene Proteins c-kit