One of the major challenges facing the field of Hematology and Oncology is that of the secondary hematologic disorders. These disorders are becoming increasingly common, at least in part because of the effectiveness of high dose cytotoxic therapy in the treatment of patients with malignant disease. As many as 10% of patients cured of malignant disease by therapy with DNA damaging agents will develop a hematologic disorder and this percentage may be double in patients who are treated with autologous stem cell transplantation as part of their curative therapy. The rapid clinical course of both secondary MDS and secondary AML makes the development of these disorders in patients already cured of one malignancy especially disturbing. While a great deal of information is available regarding a variety of molecular genetic abnormalities which have been detected in MDS and AML, little or no information is available with respect to how often multiple genetic abnormalities are present and little information is available regarding the biological consequences of these abnormalities. The lack of information in these areas severely restricts our understanding of the development of MDS and AML. The studies which will be conducted as part of this Program Project will focus on the most common molecular genetic lesions of these disorders, will study these lesions simultaneously in the same patients, the in vivo and in vitro biological characteristics of the abnormal cells will be identified and related to the genetic lesions which are present. Parallel in vitro studies will help to define the mechanisms underlying these associations. Special emphasis will be placed in two areas: 1 - on MDS and AML characterized by deletions of chromosomes 5 and/or 7 q and 2 - on aberrant cytokine production in these diseases and the role which it plays in the genesis of both MDS and AML. These two areas of particular interest, the former because the stability of these genetic lesions as the disease evolves from MDS to AML strongly suggests a key role of these lesions in the genesis of these disorders and the second because of our demonstrated ability to suppress abnormal cytokine production in vivo in patients and thus alter the behavior of both MDS and AML cells. This later ability offers the prospect of rapidly applying the results of the laboratory studies to the clinic to improve treatment outcome in both MDS and AML.
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