Therapy-related myelodysplastic syndrome (t-MDS) or acute myeloid leukemia (t-AML) is a late complication of cytotoxic therapy of both malignant and non-malignant disease. Characteristic recurring abnormalities of chromosomes 5 and/or 7 are frequently noted in t- MDS/t-AML. In our updated series, we observed loss of an entire chromosome 5 or 7, or a deletion of the long arm of [del(5q)/del(7q)] in 175 of 246 (71%) patients examined. In the previous grant period, we delineated a segment of chromosome 5 within band 5q31 that was deleted in all patients examined, and have prepared a cytogenetic map and partial genomic contig of the commonly deleted segment. We hypothesize that a tumor suppressor gene located within this segment may play r role in the pathogenesis of this disease. We now propose to use a positional cloning and candidate gene approach to identify a myeloid- leukemia gene in 5q31. The initial step will be the completion of the genomic contig of the commonly deleted segment (3-4MB interval between IL9 and D5S166). Several experimental approaches will be used to search for previously unidentified expressed sequences within the contig. Leukemia cells characterized by abnormalities of chromosome 5 will be examined for mutations of these candidate genes. If mutations of a gene on 5q are identified, we will determine the spectrum of mutations in myeloid leukemia cells, determine whether mutations of the gene are somatic or germline, and identify the consequence(s) of the mutations on the function of the gene/protein. We plan to delineate the smallest deleted segment of 7q by using cytogenetic mapping techniques to examine leukemia cells with deletions or translocations of 7q. These studies will form the basis for additional molecular studies to isolate a myeloid leukemia-related gene on 7q. Tumor suppressor genes have not been well-characterized in the hematologic malignant diseases. We hope that by analyzing recurring deletions, we can begin to evaluate the role of recessive mutations in the pathogenesis of MDS and AML, and to elucidate the relationship of previous cytotoxic therapy with mutations of genes on chromosomes 5 and 7.
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