This cooperative project proposes a study of the molecular mechanisms leading to the appearance of secondary acute nonlymphocytic leukemia (ANLL) in a group of patients previously treated with radiation and/or chemotherapy. It has almost 90 percent of patients with ANLL secondary to therapy. It is proposed to: a) Develop a series of polymorphic DNA probes located in the critical regions that are consistently deleted in chromosome 5 and 7; b) Use these probes to map the region of the deletion more precisely in each patient with a chromosome 5 or 7 deletion; c) Test the sensitivity to induced mutation of cells from individuals who develop secondary ANLL as compared to appropriate controls; d) Determine the level of 06-methylguanine transferase in cells of patients before and after treatment with cytotoxic agents, including procarbazine, which may act as methylating agents; and e) To study the conditions conducive to gene fusion and the structures of the resulting fusions. We wish to know how the treatments used induce new gene associations. The projects are integrated by their use of a common set of patients and by the attempt to correlate the data obtained in the several individual and cooperative projects into an overall picture of the changes in cells of treated cancer patients in the expectation that this may lead to an understanding of the origin of secondary malignancy. We are particularly interested in knowing whether the appearance of secondary leukemia occurs by chance or whether a class of patients is predisposed to such events. The overall project follows patients from pre-treatment through treatment and the development of secondary malignancy and as such may serve as a general model for carcinogenesis in man.
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