Secondary acute nonlymphocytic leukemia (ANLL) is a late complication that occurs in individuals exposed to cytotoxic agents for the treatment of a primary malignant or nonmalignant disease. While exposure to the cytotoxic agents is believed to cause the malignancy, we do not know why the second malignancy develops only in certain individuals, nor why it is this particular malignancy that develops. We propose to continue our studies on the role of mutagen sensitivity in the etiology of secondary ANLL. Peripheral blood lymphocytes (PBLs) obtained from patients with ANLL have been shown to have lower levels of the DNA repair protein O6-alkylguanine alkyltransferase (AGT) than do healthy controls or patients with de novo forms of ANLL. In this project, we will examine the biological importance of these reduced levels of AGT in detail, studying the cellular, cytogenetic and molecular effects of exposure to mono-and bifunctional alkylating agents in six isogenic human lymphoblastoid cell lines with AGT activities ranging from 0-25 fmol/ug DNA cells. The following questions will be addressed; 1) Are lower levels of AGT always associated with increased sensitivity to alkylation-induced mutagenicity? 2) Do different levels of AGT affect the induction of DNA and chromosome breaks by alkylating agents? 3) What are the spectra of mutations induced by alkylating agents in cells with different levels of AGT activity? Understanding the biological significance of reduced AGT activities should provide clues to the etiology of secondary ANLL.
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