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

Gideon Bollag, D. Clapp, Shane Shih, Felix Adler, You Yan Zhang, Patricia Thompson, Beverly J. Lange, Melvin H. Freedman, Frank McCormick, Tyler Jacks, Kevin Shannon

Research output: Contribution to journalArticle

425 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)144-148
Number of pages5
JournalNature Genetics
Volume12
Issue number2
DOIs
StatePublished - Feb 1996

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Neurofibromatosis 1
Juvenile Myelomonocytic Leukemia
Granulocyte-Macrophage Colony-Stimulating Factor
Neurofibromin 1
Growth
Guanosine Triphosphate
ras GTPase-Activating Proteins
GTPase-Activating Proteins
ras Proteins
Tumor Suppressor Genes
Hypersensitivity
Hydrolysis
Embryonic Structures
Neoplasms
Proteins

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells. / Bollag, Gideon; Clapp, D.; Shih, Shane; Adler, Felix; Zhang, You Yan; Thompson, Patricia; Lange, Beverly J.; Freedman, Melvin H.; McCormick, Frank; Jacks, Tyler; Shannon, Kevin.

In: Nature Genetics, Vol. 12, No. 2, 02.1996, p. 144-148.

Research output: Contribution to journalArticle

Bollag, G, Clapp, D, Shih, S, Adler, F, Zhang, YY, Thompson, P, Lange, BJ, Freedman, MH, McCormick, F, Jacks, T & Shannon, K 1996, 'Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells', Nature Genetics, vol. 12, no. 2, pp. 144-148. https://doi.org/10.1038/ng0296-144
Bollag, Gideon ; Clapp, D. ; Shih, Shane ; Adler, Felix ; Zhang, You Yan ; Thompson, Patricia ; Lange, Beverly J. ; Freedman, Melvin H. ; McCormick, Frank ; Jacks, Tyler ; Shannon, Kevin. / Loss of NF1 results in activation of the Ras signaling pathway and leads to aberrant growth in haematopoietic cells. In: Nature Genetics. 1996 ; Vol. 12, No. 2. pp. 144-148.
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