Nf1 and Gmcsf interact in myeloid leukemogenesis.
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.
Birnbaum
R A
RA
Department of Pediatrics, University of California, San Francisco 94143-0519, USA.
O'Marcaigh
A
A
Wardak
Z
Z
Zhang
Y Y
YY
Dranoff
G
G
Jacks
T
T
Clapp
D W
DW
Shannon
K M
KM
D019264:Adoptive Transfer; D000818:Animals; D002455:Cell Division; D002648:Child; D003433:Crosses, Genetic; D005260:Female; D016514:Genes, Neurofibromatosis 1; D020022:Genetic Predisposition to Disease; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000172:deficiency / Q000235:genetics* / Q000494:pharmacology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006579:Heterozygote; D006801:Humans; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics* / Q000473:pathology; D008099:Liver / Q000196:embryology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D025542:Neurofibromin 1; D011506:Proteins / Q000235:genetics*
D025542:Neurofibromin 1; D011506:Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor