Nf1 regulates hematopoietic progenitor cell growth and ras signaling in response to multiple cytokines

You Yan Zhang, Terry A. Vik, John W. Ryder, Edward F. Srour, Tyler Jacks, Kevin Shannon, D. Wade Clapp

Research output: Contribution to journalArticle

123 Scopus citations

Abstract

Neurofibromin, the protein encoded by the NF1 tumor-suppressor gene, negatively regulates the output of p21(ras) (Ras) proteins by accelerating the hydrolysis of active Ras-guanosine triphosphate to inactive Ras-guanosine diphosphate. Children with neurofibromatosis type 1 (NF1) are predisposed to juvenile chronic myelogenous leukemia (JCML) and other malignant myeloid disorders, and heterozygous Nf1 knockout mice spontaneously develop a myeloid disorder that resembles JCML. Both human and murine leukemias show loss of the normal allele. JCML cells and Nf1(-/-) hematopoietic cells isolated from fetal livers selectively form abnormally high numbers of colonies derived from granulocyte-macrophage progenitors in cultures supplemented with low concentrations of granulocyte-macrophage colony stimulating factor (GM-CSF). Taken together, these data suggest that neurofibromin is required to downregulate Ras activation in myeloid cells exposed to GM-CSF. We have investigated the growth and proliferation of purified populations of hematopoietic progenitor cells isolated from Nf1 knockout mice in response to the cytokines interleukin (IL)-3 and stem cell factor (SCF), as well as to GM-CSF. We found abnormal proliferation of both immature and lineage- restricted progenitor populations, and we observed increased synergy between SCF and either IL-3 or GM-CSF in Nf1(-/-) progenitors. Nf1(-/-) fetal livers also showed an absolute increase in the numbers of immature progenitors. We further demonstrate constitutive activation of the Ras-Raf-MAP (mitogen- activated protein) kinase signaling pathway in primary c-kit+ Nf1(-/-) progenitors and hyperactivation of MAP kinase after growth factor stimulation. The results of these experiments in primary hematopoietic cells implicate Nf1 as playing a central role in regulating the proliferation and survival of primitive and lineage-restricted myeloid progenitors in response to multiple cytokines by modulating Ras output.

Original languageEnglish (US)
Pages (from-to)1893-1902
Number of pages10
JournalJournal of Experimental Medicine
Volume187
Issue number11
DOIs
StatePublished - Jun 1 1998

Keywords

  • Cytokines
  • Granulocyte/ macrophage colony-stimulating factor
  • Hematopoietic progenitor
  • Neurofibromin
  • Ras

ASJC Scopus subject areas

  • Immunology

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