A specific chromosomal abnormality, the Philadelphia translocation, is characteristic of leukemic cells of over 95% of all patients with chronic myelogenous leukemia.The Philadelphia chromosome, generated by this translocation, is the result of a break occurring within a gene designated the bcr gene, on chromosome 22; sequence 3' of the breakpoint are translocated to chromosome 9, from which the c-abl oncogene is transferred into the bcr gene. The resulting chimeric bcr-c-abl gene produces a chimeric mRNA and abnormal abl protein. Three bcr-homologous loci have been molecularly cloned during previous research; in addition, two different abl homologous sequences have been isolated. The major objective of this project is to determine the possible involvement of bcr and abl homologous sequences in human cancer. The chromosomal location of the bcr-related and the abl- related genes will be determined and cDNAs will be isolated from loci found to be actively transcribed genes. Such genes will be further characterized by nucleotide sequencing and a comparison with the bcr and abl genes. In addition, the deduced amino acid sequence of the related genes will be used to search for proteins with identical and/or homologous primary structures. This information might be valuable for the assignment of a putative cellular function for the normal bcr and abl protein products. Probes isolated from the cDNAs and/or corresponding cloned genomic DNA sequences will be used to screen DNAs from leukemias, lymphomas and solid tumors for rearrangements and translocations using conventional and pulsed-field gradient gel electrophoresis. The combined gel electrophoresis techniques followed by Southern hybridization should allow the detection of genomic abnormalities in DNA stretches of up to 300 kb. In each instance where the association of a member of the bcr or abl gene family with a specific malignancy can be established, further studies to characterize the abnormality and to determine the frequency of involvement will be initiated.
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