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You-Yan Zhang^*,||, Terry A. Vik^*,||, John W. Ryder^*,||, Edward F. Srour^*,||,, Tyler Jacks^¶, Kevin Shannon^**, and D. Wade Clapp^*,,||

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

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.

Key Words: neurofibromin • hematopoietic progenitor • cytokines • Ras • granulocyte/ macrophage colony–stimulating factor

Abbreviations used: CFC, colony-forming cells; GAP, GTPase-activating protein; HPP, high proliferating potential; JCML, juvenile chronic myelogenous leukemia; LPP, low proliferating potential; MAP, mitogen-activated protein; MBP, myelin basic protein; MEK, MAP kinase/extracellular signal-regulated kinase; NF1, neurofibromatosis type 1; SCF, stem cell factor.

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