The human BCR gene and the ABL oncogene are specifically involved in and are directly or indirectly causative of Philadelphia-chromosome positive leukemia. Two genes related to the ABL oncogene (Abrel-2 and FER), as well as one actively transcribed gene related to the BCR gene (ABR) have been identified. The ABR gene is located on chromosome 17p13 and FER on chromosome 5q21-22. Both locations coincide with regions identified previously as being involved in human tumorigenesis; the region 17p13 is associated with chromosome 17 abnormalities found in CML and 5q21-22 is the location of the familial adenomatous polyposis locus. In one part of this application they propose to investigate the putative involvement of these genes by Southern blot, FIGE, linkage analysis (in collaboration with Dr. Vogelstein), in situ hybridization (in collaboration with Dr. Morris) and mapping. In the second component of this application they propose to investigate the structure of ARG-related gene(s), the Brel-3 region and the FER gene and the function of FER. The genomic organization of the FER gene is likely to be complex and at least 3 different-sized transcripts have been identified; the FER promoter will be cloned and sequenced to identify regulatory regions. The FER gene product was identified as a nuclear protein-tyrosine kinase; the signals responsible for transport of FER into the nucleus will be determined by constructing deletion mutants. Some experiments will be aimed at unraveling its function in the nucleus (in collaboration with Dr. Ferris): FER phosphorylation will be assayed during the cell cycle and its possible function as a substrate for cdc2 will be investigated. The role of FER in IL-3 signal transduction will also be examined. The overall aim of this project is to investigate the role of BCR and ABL-related genes in human tumorigenesis and to understand the role of the FER gene in cellular regulatory processes. The ultimate goal is to identify and understand processes by which oncogenes can convert normal cells to malignant cells.