Project III is devoted to the study of poor prognosis AML and its evolution from a myelodysplastic state. The common molecular genetic abnormalities present in MDS and AML will be identified and compared so that combinations of abnormalities present in AML but not in MDS can be identified. These comparisons will utilize two strategies: a comparison of groups of patients and the serial study of individual patients from the time at which MDS is diagnosed through the time that AML has appeared. The goals of these studies are threefold: 1: to develop and identify the combinations of genetic lesions which are associated with the development of AML 2- to identify the biologic effects of these lesions on hemopoietic cells; and 3-to relate the clinical characteristics of the diseases and their response to treatment to the genetic lesions and their biological consequences. Specific in vitro studies designed to directly test the observed relationship between the various observed phenomena will be performed as well. At the clinical level we are particularly interested in the phenomenon of regrowth resistance as a cause of remission induction failure and also in the association of a return of myelodysplastic hemopoiesis after therapy [instead of either leukemia or normal cells] with short leukemia-free remissions. We hypothesize that aberrant cytokine production by leukemia cells and together with abnormal responses to cytokine production, both as a consequence of the genetic lesions which are present in AML and in MDS, play a major role in both regrowth resistance of AML and also in the early recurrence of leukemia in patients who achieve 'myelodysplastic' remission after treatment for AML. We will document the involvement of specific genetic abnormalities in both processes and will develop strategies for suppressing abnormal cytokine production and/or the abnormal responses AML cells to cytokines. These strategies will be tested in patients and the successful ones will be prospectively tested in pilot clinical trials. The studies proposed here hold out the promise of the development of an understanding of the impact of genetic anbormalitites on the cell and clinical biology of AML and also the promise of facilitating the development of the means to suppress the biologic consequences of these abnormalities so as to improve treatment outcome.
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