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

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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

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Keywords

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

ASJC Scopus subject areas

  • Immunology

Cite this

Nf1 regulates hematopoietic progenitor cell growth and ras signaling in response to multiple cytokines. / Zhang, You Yan; Vik, Terry A.; Ryder, John W.; Srour, Edward F.; Jacks, Tyler; Shannon, Kevin; Clapp, D. Wade.

In: Journal of Experimental Medicine, Vol. 187, No. 11, 01.06.1998, p. 1893-1902.

Research output: Contribution to journalArticle