This cooperative project proposes a study of the molecular genetic mechanisms leading to the appearance of myelodysplasia and/or leukemia in a group of patients previously treated with radiation and/or chemotherapy. The program started with the observation that almost 90% of patients with acute myeloid leukemia secondary to therapy (t-AML) had losses or deletions of chromosome 5 or 7. The studies of the past five years have resulted in the development of more specific hypotheses on the etiology of t-AML. We propose: a) to provide a molecular-cytogenetic analysis of the abnormalities of chromosomes 5 and 7 in malignant myeloid disorders; b) to identify and clone a putative leukemia suppressor or antileukemia gene (ALG) hypothesized to be present on chromosome 5; c) to determine the location of the translocation breakpoints involving chromosome band 11q23 relative to the location of topoisomerase binding sites in t-AML patients who have received epipodophyllotoxins; and d) to determine the role of EGR1, an early growth response gene, mapping to the critical region of chromosome 5, in myeloid differentiation and tumorigenesis. The projects are integrated by their use of a common set of patients and by the desire to synthesize the data generated by the different projects into an overall picture of the changes in the cells of treated cancer patients in the expectation that this may lead to an understanding of the origin of therapy-related leukemia. The overall project follows patients from pretreatment through treatment and follow-up and the ultimate development of a secondary hematologic malignancy and as such may provide a general description of carcinogenesis in humans.
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