Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells.
Individuals with neurofibromatosis type 1 (NF1) are predisposed to certain cancers including juvenile chronic myelogenous leukaemia (JCML). The NF1 tumour-suppressor gene encodes a protein (neurofibromin) that accelerates GTP hydrolysis on Ras proteins. Here we show that primary leukaemic cells from children with NF1 show a selective decrease in NF1-like GTPase activating protein (GAP) activity for Ras but retain normal cellular GAP activity. Leukaemic cells also show an elevated percentage of Ras in the GTP-bound conformation. JCML cells are hypersensitive to granulocyte-macrophage colony stimulating factor (GM-CSF), and we observed a similar pattern of aberrant growth in haematopoietic cells from Nf1-/- mouse embryos. These data define a specific role for neurofibromin in negatively regulating GM-CSF signaling through Ras in haematopoietic cells and they suggest that hypersensitivity to GM-CSF may be a primary event in the development of JCML.
Bollag
G
G
Onyx Pharmaceuticals, Richmond, California 94806, USA.
Clapp
D W
DW
Shih
S
S
Adler
F
F
Zhang
Y Y
YY
Thompson
P
P
Lange
B J
BJ
Freedman
M H
MH
McCormick
F
F
Jacks
T
T
Shannon
K
K
D000818:Animals; D002455:Cell Division; D002478:Cells, Cultured; D002648:Child; D020690:GTPase-Activating Proteins; D016514:Genes, Neurofibromatosis 1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D051379:Mice; D009456:Neurofibromatosis 1 / Q000378:metabolism* / Q000473:pathology; D025542:Neurofibromin 1; D011506:Proteins / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D020703:ras GTPase-Activating Proteins; D018631:ras Proteins / Q000378:metabolism / Q000502:physiology*
D020690:GTPase-Activating Proteins; D025542:Neurofibromin 1; D011506:Proteins; D020703:ras GTPase-Activating Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006160:Guanosine Triphosphate; D018631:ras Proteins