LOSS OF THE NORMAL NF1 ALLELE FROM THE BONE-MARROW OF CHILDREN WITH TYPE-1 NEUROFIBROMATOSIS AND MALIGNANT MYELOID DISORDERS

Background. Children with type 1 neurofibromatosis (NF-1) are at incre ased risk for malignant myeloid disorders. Analysis of the NF-1 gene ( NF1) suggests that the function of its product, neurofibromin, is redu ced in affected persons and that NF1 belongs to the tumor-suppressor c lass of recessive cancer genes. This model is consistent with evidence that neurofibromin accelerates the intrinsic guanosine triphosphate-h ydrolyzing activity of the Ras family of regulatory proteins. Loss of constitutional heterozygosity has not been reported in the benign tumo rs associated with NF-1, however, and has only been detected in a few malignant neural-crest tumors and in some tumor-derived cell lines. Me thods. We studied DNA extracted from the bone marrow of 11 children wi th NF-1 in whom malignant myeloid disorders developed and from parenta l leukocytes. We used a series of polymorphic markers within and near NF1 to determine whether leukemogenesis was associated with structural alterations of the gene. Results. Bone marrow samples from five patie nts showed loss of heterozygosity. In each case, the NF1 allele was in herited from a parent with NF-1 and the normal allele was deleted. Con clusions. 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.