BACKGROUND Young patients with neurofibromatosis type 1 (NF1) are at increased risk of developing various malignancies, most of which are myeloid disorders. The observed loss of NF1 allele in the myeloid malignancies of NF1 patients suggests a role of NF1 as a tumor suppressor gene. Loss of 17p was found to be quite frequent in neural crest tumors from patients with NF1, raising the possibility of p53 tumor suppressor gene involvement in other NF1-related tumors. METHODS The authors studied mutations in the NF1 and p53 genes, using loss of heterozygosity, single strand conformation polymorphism, heteroduplex and sequencing analyses. RESULTS An NF1 germline mutation was identified in exon 31 of a child who developed juvenile chronic myelogenous leukemia (JCML). The mutation was segregated within the proband's family. A 14bp deletion at exon 6 of the p53 gene was observed when JCML was diagnosed, and the wild-type p53 allele was lost during progression of the disease. No loss of the normal NF1 allele could be detected. CONCLUSIONS A germline mutation in the NF1 gene and sequential inactivation of p53 alleles in the malignant clone of JCML raise the possibility of a correlation between NF1 and p53 genes in the tumorigenesis of JCML.