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

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

Research output: Contribution to journalArticle

118 Citations (Scopus)

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

Fingerprint

Juvenile Myelomonocytic Leukemia
Neurofibromin 1
Granulocyte-Macrophage Colony-Stimulating Factor
Hematopoietic Stem Cells
Cytokines
Stem Cell Factor
Interleukin-3
Growth
Knockout Mice
Proto-Oncogene Proteins p21(ras)
ras Proteins
Granulocyte-Macrophage Progenitor Cells
Neurofibromatosis 1
Guanosine
Diphosphates
Liver
Myeloid Cells
Guanosine Triphosphate
Mitogen-Activated Protein Kinases
Tumor Suppressor Genes

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; Ryder, John W.; Srour, Edward; Jacks, Tyler; Shannon, Kevin; Clapp, D.

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

Research output: Contribution to journalArticle

@article{ac79e456409d43af99852fffc1a848c9,
title = "Nf1 regulates hematopoietic progenitor cell growth and ras signaling in response to multiple cytokines",
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.",
keywords = "Cytokines, Granulocyte/ macrophage colony-stimulating factor, Hematopoietic progenitor, Neurofibromin, Ras",
author = "Zhang, {You Yan} and Terry Vik and Ryder, {John W.} and Edward Srour and Tyler Jacks and Kevin Shannon and D. Clapp",
year = "1998",
month = "6",
day = "1",
doi = "10.1084/jem.187.11.1893",
language = "English",
volume = "187",
pages = "1893--1902",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "11",

}

TY - JOUR

T1 - Nf1 regulates hematopoietic progenitor cell growth and ras signaling in response to multiple cytokines

AU - Zhang, You Yan

AU - Vik, Terry

AU - Ryder, John W.

AU - Srour, Edward

AU - Jacks, Tyler

AU - Shannon, Kevin

AU - Clapp, D.

PY - 1998/6/1

Y1 - 1998/6/1

N2 - 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.

AB - 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.

KW - Cytokines

KW - Granulocyte/ macrophage colony-stimulating factor

KW - Hematopoietic progenitor

KW - Neurofibromin

KW - Ras

UR - http://www.scopus.com/inward/record.url?scp=0032101134&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032101134&partnerID=8YFLogxK

U2 - 10.1084/jem.187.11.1893

DO - 10.1084/jem.187.11.1893

M3 - Article

VL - 187

SP - 1893

EP - 1902

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 11

ER -