Therapy-related myelodysplastic syndrome (t-MDS) or acute myeloid leukemia (t-AML) is late complications of the successful use of cytotoxic therapy for the treatment of malignant diseases. Several clinical and biological subsets of t-MDS/t-AML have been recognized, which correlate with the therapy received for the primary disease. The most common type presents after a latency of about 5 years in patients who received alkylating agents, and is characterized by loss or deletion of chromosomes 5 and/or 7. In contrast, patients who develop t-AML following treatment with drugs targeting topoisomerase II typically have recurring translocations of the MLL gene at 11q23, or the RUNX1/AML1 gene at 21q22. The goal of this program project is to elucidate the molecular mechanisms leading to t-MDS/t-AML. We propose four integrated projects that focus on the role of chromosomal abnormalities in malignant transformation. Drs. Rowley and Zeleznik-Le are devoting their efforts to the analysis of recurring translocations involving MLL and RUNX1. Dr. Rowley will focus on a structural analysis of MLL and RUNX1 and their partner genes, AF9 and CBP, and ETO and MDS1, respectively. The overall goal of these studies is to identify structural elements within MLL, RUNX1, and their partner genes, which could be involved in mediating chromosomal translocations. Dr. Zeleznik-Le will examine the mechanisms by which MLL-fusion proteins mediate malignant transformation. She will focus on the MLL-CBP fusion gene involved in t-MDS. Dr. Le Beau will focuses on the identification of a myeloid leukemia tumor suppressor gene on 5q. In complementary studies, Dr. Shannon will focuses on the identification and functional analysis of candidate tumor suppressor genes on 7q. In addition, both investigators will evaluate alternative mechanisms other than tumor suppressor genes, in the pathogenesis of t-MDS/t-AML with abnormalities of chromosomes 5 or 7. The projects utilize a Patient Access, Data Management and Cell Storage Core. The Core insures an orderly flow of leukemia specimens to the four projects, and the collection, and analysis of critical clinical, biological, and statistical data. The Program Project is integrated by its use of a common set of patients for molecular analysis with the goal of developing an improved understanding of the etiology of t-AML.
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