The objectives of this research are to identify specific changes in oncogene chromatin which relate to various hematologic malignancies, to determine if such changes can be employed in a clinically relevant method to assess the state of oncogene chromatin in patients at various points in the clinical course of a hematologic malignancy, and to determine if such changes are either predictive of the future course of a hematologic malignancy or can be employed as a diagnostic assay to identify early stages of a hematologic malignancy. Specifically, three oncogenes that have been implicated in human hematologic malignancies are the focus of this project: c-abi chromatin will be studied and correlated to the course of chronic myelogenous leukemia; c-myc chromatin will be studied and correlated to the course of B-cell lymphomas; and c-mos chromatin will be studied and correlated to the course of acute myelogenous leukemia. Appropriate human cell lines, e.g., K562 and HL-60, will be employed as model systems. Oncogene chromatin organization in human leukemia/lymphoma cells and in appropriate cell lines will be assessed by DNAse I and S1 digestion assays. Unique patterns of DNAse I sensitivity, as well as novel hypersensitive sites, will be sought by restriction endonuclease digestion, Southern blotting, and probing with specific oncogene DNA sequences. Leukemia/lymphoma specific changes in oncogene chromatin will be studied in individual patients at various points in the clinical evolution of their hematologic malignancy as well as in group studies. Methods will be devised to determine whether specific oncogene chromatin changes can be used in a clinically relevant manner to predict the course of a patient's illness or as a diagnostic assay for early disease. An improvement in diagnostic and prognostic assessment by this approach may allow earlier or more precise therapeutic endeavors for patients with hematologic malignancies. (K)
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