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J. Exp. Med.,
Volume 187, Number 11, June 1, 1998 1893-1902
By
§
From the * Department of Pediatrics, the 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 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
/ 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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