Background: The risk of malignant myeloid disorders in young children with neurofibromatosis type 1 is 200 to 500 times the normal risk. The gene for neurofibromatosis type 1 (NF1) encodes neurofibromin, a protein that negatively regulates signals transduced by Ras proteins. Genetic and biochemical data support the hypothesis that NF1 functions as a tumor-suppressor gene in immature myeloid cells, but inactivation of both NF1 alleles has not been demonstrated in leukemic cells from patients with neurofibromatosis type 1.
Methods: Using an in vitro transcription and translation system, we screened bone marrow samples from 18 children with neurofibromatosis type 1 and myeloid disorders for NF1 mutations that cause a truncated protein. Mutations were confirmed by direct sequencing of genomic DNA from the patients, and from their affected parents, in cases of familial neurofibromatosis type 1.
Results: Specimens from 9 of the 18 children contained abnormal peptide fragments, and truncating mutations of the NF1 gene were found in specimens from 8 of these children. The normal NF1 allele was absent in bone marrow samples from five of the eight children. We detected the same mutation in DNA from the affected parent of each child with familial neurofibromatosis type 1.
Conclusions: Both alleles of the NF1 gene are inactivated in leukemic cells in some patients with neurofibromatosis type 1. NF1 appears to function as a tumor-suppressor gene in immature myeloid cells.