Background Children with type 1 neurofibromatosis (NF-1) areat increased risk for malignant myeloid disorders. Analysisof the NF-1 gene (NF1) suggests that the function of its product,neurofibromin, is reduced in affected persons and that NF1 belongsto the tumor-suppressor class of recessive cancer genes. Thismodel is consistent with evidence that neurofibromin acceleratesthe intrinsic guanosine triphosphate-hydrolyzing activity ofthe Ras family of regulatory proteins. Loss of constitutionalheterozygosity has not been reported in the benign tumors associatedwith NF-1, however, and has only been detected in a few malignantneural-crest tumors and in some tumor-derived cell lines.
Methods We studied DNA extracted from the bone marrow of 11children with NF-1 in whom malignant myeloid disorders developedand from parental leukocytes. We used a series of polymorphicmarkers within and near NF1 to determine whether leukemogenesiswas associated with structural alterations of the gene.
Results Bone marrow samples from five patients showed loss ofheterozygosity. In each case, the NF1 allele was inherited froma parent with NF-1 and the normal allele was deleted.
Conclusions These data provide evidence that NF1 may functionas a tumor-suppressor allele in malignant myeloid diseases inchildren with NF-1 and that neurofibromin is a regulator ofRas in early myelopoiesis.
Source Information
From the Department of Pediatrics, University of California, San Francisco (K.M.S., D.P., K.O.); the Department of Pathology, University of Texas Health Science Center, San Antonio (P.O.); Onyx Pharmaceuticals, Richmond, Calif. (G.A.M., F.M.); and the Division of Pediatric Oncology, Children's National Medical Center, Washington, D.C. (P.D.).
Address reprint requests to Dr. Shannon at the Department of Pediatrics, University of California, Rm. U-432, San Francisco, CA 94143-0724.
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