Leukemic potential of doubly mutant Nf1 and Wv hematopoietic cells.
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.
Ingram
David A
DA
Indiana University School of Medicine, Herman B. Wells Center for Pediatric Research, Department of Microbiology/Immunology, Indianapolis, IN 46202, USA. dingram@iupui.edu
Wenning
Mary Jo
MJ
Shannon
Kevin
K
Clapp
D Wade
DW
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
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