Children with type 1 neurofibromatosis (NF-1) are at increased risk for malignant myeloid disorders. Analysis of the NF-1 gene (NF1) suggests that the function of its product, neurofibromin, is reduced in affected persons and that NF1 belongs to the tumor-suppressor class of recessive cancer genes. This model is consistent with evidence that neurofibromin accelerates the intrinsic guanosine triphosphate-hydrolyzing activity of the Ras family of regulatory proteins. Loss of constitutional heterozygosity has not been reported in the benign tumors associated with NF-1, however, and has only been detected in a few malignant neural-crest tumors and in some tumor-derived cell lines.

We studied DNA extracted from the bone marrow of 11 children with NF-1 in whom malignant myeloid disorders developed and from parental leukocytes. We used a series of polymorphic markers within and near NF1 to determine whether leukemogenesis was associated with structural alterations of the gene.

Bone marrow samples from five patients showed loss of heterozygosity. In each case, the NF1 allele was inherited from a parent with NF-1 and the normal allele was deleted.

These data provide evidence that NF1 may function as a tumor-suppressor allele in malignant myeloid diseases in children with NF-1 and that neurofibromin is a regulator of Ras in early myelopoiesis.