title: Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells.
abstract: 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.
authors.affiliation: Onyx Pharmaceuticals, Richmond, California 94806, USA.
authors.forename: G
authors.initials: G
authors.lastname: Bollag
authors.forename: D W
authors.initials: DW
authors.lastname: Clapp
authors.forename: S
authors.initials: S
authors.lastname: Shih
authors.forename: F
authors.initials: F
authors.lastname: Adler
authors.forename: Y Y
authors.initials: YY
authors.lastname: Zhang
authors.forename: P
authors.initials: P
authors.lastname: Thompson
authors.forename: B J
authors.initials: BJ
authors.lastname: Lange
authors.forename: M H
authors.initials: MH
authors.lastname: Freedman
authors.forename: F
authors.initials: F
authors.lastname: McCormick
authors.forename: T
authors.initials: T
authors.lastname: Jacks
authors.forename: K
authors.initials: K
authors.lastname: Shannon
mesh_terms: 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*
chemical_list: 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