MUTATIONAL ANALYSIS OF N-RAS AND GAP-RELATED DOMAIN OF THE NEUROFIBROMATOSIS TYPE-1 GENE IN CHRONIC MYELOGENOUS LEUKEMIA

RAS mutations can be detected in a variable number of patients with my eloproliferative disorders such as myelodysplastic syndromes and acute myeloid leukemia, but are rare events in chronic myelogenous leukemia in chronic phase. However, there is good evidence supporting the invo lvement of RAS signalling pathway in CML and this could be due to alte rations in RAS activity regulatory proteins. The neurofibromatosis (NF 1) gene down- regulates the RAS signal transduction pathway through th e inhibitory function of its GAP-related domain (GRD) on RAS protein. The loss or alteration of neurofibromin (the NF1 protein) may produce a disfunction similar to point mutations in the RAS gene resulting in the permanent stimulation of the RAS signal transduction pathway. Muta tions involving the GRD region of the NF1 gene (GRD-NF1) have been des cribed in a variety of tumors such as colon carcinoma and astrocytoma. Germline mutations and deletions in the NF1 gene, as seen in neurofib romatosis type I, are also associated with certain myeloid disorders. In the present work, we sought to identify mutations in the codons 12/ 13 and 61 of RAS gene and in the Lys-1423 codon of GRD-NF1, which are well known hot spots in these genes, in a group of 36 adults and ten c hildren with chronic myelogenous leukemia in chronic phase and blast c risis. Using the PCR-SSCP and the allele-specific restriction assay (A SRA) techniques, we were not able to observe any RAS or NF1 detectable mutation. These findings suggest that RAS and GRD-NF1 mutations are n ot involved either in chronic phase or in the progression to blast cri sis in chronic myelogenous leukemia in adults and children. (C) 1998 E lsevier Science Ltd. All rights reserved.