ANALYSIS OF MUTATIONS OF NEUROFIBROMATOSIS TYPE-1 GENE AND N-RAS GENEIN ACUTE MYELOGENOUS LEUKEMIA

Neurofibromatosis type 1 (NF1) gene is a tumor suppressor gene, and th e NF1 gene product, neurofibromin, can downregulate the N-ras gene. Be cause the N-ras gene is often mutated in acute myelogenous leukemia (A ML), we wondered if the NF1 gene might be mutated in those AML samples not having N-ras mutations. We investigated the mutational status of the N-ras gene and the FLR exon of codons 1371-1423 of the open readin g frame of the full-length NF1 cDNA, which has a strong homology with the mammalian ras GTPase-activating protein (GAP), especially for a st retch of three consecutive amino acids (F, L, R), by single-strand con formation polymorphism analysis and direct sequencing in samples from patients with AML. Of 48 AML patients, 10 (21%) had point (missense) m utations of the N-ras gene involving codons 12, 13 and 61. However, mu tations in the FLR exon of the NF1 gene were not detected in any of th e AML samples. We also examined the difference of clinical response to induction therapy between AML patients with and without N-ras mutatio n. A significantly lower rate of complete remission was noted in indiv iduals with the N-ras gene mutations. These results suggest that mutat ion of the NF1 gene, at least in the FLR exon, is very rare in AML and the NF1 gene probably is not a functional complement of the N-ras gen e mutation. The presence of N-ras gene mutation may be associated with a lower clinical response to antileukemic therapy.