title: Leukemic potential of doubly mutant Nf1 and Wv hematopoietic cells.
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.
authors.affiliation: Indiana University School of Medicine, Herman B. Wells Center for Pediatric Research, Department of Microbiology/Immunology, Indianapolis, IN 46202, USA. dingram@iupui.edu
authors.forename: David A
authors.initials: DA
authors.lastname: Ingram
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Wenning
authors.forename: Kevin
authors.initials: K
authors.lastname: Shannon
authors.forename: D Wade
authors.initials: DW
authors.lastname: Clapp
mesh_terms: D000483:Alleles; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003114:Colony-Forming Units Assay; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D018390:Gene Targeting; D016514:Genes, Neurofibromatosis 1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D007375:Interleukin-1 / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D015479:Leukemia, Myelomonocytic, Acute / Q000235:genetics*; D008099:Liver / Q000166:cytology / Q000196:embryology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009196:Myeloproliferative Disorders / Q000209:etiology*; D025542:Neurofibromin 1 / Q000172:deficiency*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000502:physiology*; D011828:Radiation Chimera; D011994:Recombinant Proteins / Q000494:pharmacology; D019089:Stem Cell Factor / Q000494:pharmacology
chemical_list: D007375:Interleukin-1; D007377:Interleukin-3; D025542:Neurofibromin 1; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D016173:Macrophage Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019009:Proto-Oncogene Proteins c-kit