Nf1 Regulates Hematopoietic Progenitor Cell Growth and Ras Signaling in Response to Multiple Cytokines
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Neurofibromin, the protein encoded by the NF1 tumor-suppressor gene, negatively regulates the output of p21ras (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.
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Nf1 deficiency induces a myeloproliferative disorder in murine models.
“Consistent with this, Nf1 deficiency induces a myeloproliferative disorder in murine models (8,9).”
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- Authors
- Zhang, Y.-Y., Vik, T. A., Ryder, J. W., Srour, E. F., Jacks, T., Shannon, K., & Wade Clapp, D.
- Affiliations
- From the *Department of Pediatrics, the ‡Department of Microbiology and Immunology, the §Department of Medicine, and ‖The Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana 46202; the ¶Howard Hughes Medical Institute and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; and the **Department of Pediatrics, University of California San Francisco, San Francisco, California 94143
- Howard Hughes Medical Institute (US)
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 1998-06-01
- Volume
- 187
- Issue
- 11
- Pages
- 1893-1902
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2212307
- OpenAlex
- W2156597055
- Cited by
- 150
- References
- 70
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 1 · 2023: 3 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 3 · 2017: 2 · 2016: 4 · 2015: 2 · 2014: 2 · 2013: 3 · 2012: 6
- FWCI
- 6.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-sa)
- Funders
- National Cancer Institute (R29 CA74177-01, R29CA074177)
- National Institute of Diabetes and Digestive and Kidney Diseases (P50DK049218)
- Topics
- Health Sciences › Medicine › Neurology › Neurofibromatosis and Schwannoma Cases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- neurofibromin, Ras signaling, hematopoietic progenitor cells, juvenile myelomonocytic leukemia, neurofibromatosis type 1, GM-CSF, interleukin-3, stem cell factor, cytokine synergy
- MeSH terms
- Animals, Cell Division, Female, Hematopoietic Stem Cells, Interleukin-3, Macrophages, Male, Mice, Inbred C57BL, Proteins, Signal Transduction, Granulocyte-Macrophage Colony-Stimulating Factor, Proto-Oncogene Proteins p21(ras), Calcium-Calmodulin-Dependent Protein Kinases, Stem Cell Factor, Neurofibromin 1, Mice
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