Virtually all subjects affected with NF1 develop multiple benign neurofibromas, which are tumors of superficial and deep peripheral nerves that increase in number with age, along with pigmentation changes of café au lait macules, axillary/inguinal freckling, and hamartomas of the iris of the eye (2). Neurofibromas are unpredictable with regards to number, location, rate of growth, and potential for malignant transformation. Additional complications unrelated to neurofibroma development are legion, and include learning disabilities, scoliosis and other bone abnormalities, optic glioma, and malignancies of various organ systems, such as malignant peripheral nerve sheath tumors (MPNST), rhabdomyosarcoma, and myeloid leukemias (3). Although a deletion or other constitutional inactivating mutation of one NF1 allele predisposes to benign or malignant tumorigenesis, a somatic inactivating mutation of the remaining NF1 allele in a tumor progenitor cell is an early, if not initiating, event in most, if not all, NF1-associated tumors. The tumor progenitor cell of the cellularly heterogeneous neurofibroma and the MPNST is the Schwann cell (4). A second requirement for neurofibroma development in a mouse model is the presence of heterozygous Nf1+I~ murine cells in the micro-tumor environment (4). The requirement of different neurofibromin levels in target cells vs supportive cells results in modulation of the RAS signaling pathway, as neurofibromin is a guanosine-5'-triphosphatase (GTPase)-activating protein that catalyzes the conversion of active RAS-GTP to inactive RAS-GDP (5). The requirement for Nf1 heterozygosity in the mouse brain for the development of optic nerve glioma by Nf1 ablated astrocytes (6) extends the emerging paradigm that neurofibromin haploinsufficiency in cells of the micro-tumor environment is critical.
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