Specific mutations occurring in certain cellular genes(proto- oncogenes) may be important in the initiation and development of human cancers. Point mutations that occur in various members of the ras family of proto-oncogenes have been extensively studied and may be present in some 10-30% of various human malignancies. Despite the extraordinary research interest in such ras mutations, a rigorous, comprehensive study relating such point mutations to stage and development of the malignancy, response to chemotherapy, and prognosis has not been performed in any human cancer. This proposal involves such a study of human myeloid leukemia, which has been reported to be associated with point mutations in the N-ras protooncogene in some 25-50% of cases. We have developed an experimental protocol for directly sequencing critical codons of the N-ras proto-oncogene. This approach is fast, requires relatively few cells, and is capable of screening a large number of samples. Using this protocol we will determine the following: 1. What is the frequency of N-ras mutations in acute and chronic myeloid leukemia? 2. At what stage in the development of the leukemia do such N-ras mutations occur? 3. Is there any correlation between the presence of such point mutations and the leukemic phenotype, response to chemotherapy, and overall prognosis? Although these proposed studies are restricted to human myeloid leukemia, nevertheless ras mutations may play a significant role in the development of many different types of human cancers. Thus these studies relating N-ras mutations to the multistage development and pathogenesis of human myeloid leukemia may also have direct relevance to the development of other types of human malignancies.
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