Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells

Nat Genet. 1996 Feb;12(2):144-8. doi: 10.1038/ng0296-144.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Division
  • Cells, Cultured
  • Child
  • GTPase-Activating Proteins
  • Genes, Neurofibromatosis 1
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Guanosine Triphosphate / metabolism
  • Hematopoietic Stem Cells / pathology*
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Mice
  • Neurofibromatosis 1 / metabolism*
  • Neurofibromatosis 1 / pathology
  • Neurofibromin 1
  • Proteins / metabolism
  • Proteins / physiology*
  • Signal Transduction / physiology
  • ras GTPase-Activating Proteins
  • ras Proteins / metabolism
  • ras Proteins / physiology*


  • GTPase-Activating Proteins
  • Neurofibromin 1
  • Proteins
  • ras GTPase-Activating Proteins
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Guanosine Triphosphate
  • ras Proteins