ONCOGENES IN HUMAN HEMATOLOGIC MALIGNANCIES

Recent studies suggest a role for oncogenes in the pathogenesis of human malignancies. The goal of this project is to examine the structure, organization, and expression of oncogenes in human leukemias and lymphomas. Our specific aims are to: 1) Examine the abl oncogene in a cell line (K562) derived from a patient with chronic myelogenous leukemia and containing an amplified abl oncogene. We intend to determine the copy number and extent of the amplified unit, whether the amplification is tandem or dispersed, and to define the 5 feet and 3 feet sequences flanking the amplified unit. We will also examine K562 cells which are induced to differentiate, and with different proliferative capacities to see if the structure and expression of the abl oncogene is different in these cells. 2) Examine the translocated abl oncogene on the Philadelphia chromosome (Ph1) in patients with chronic myelogenous leukemia. We intend to identify the junction fragment between the translocated abl gene and chromosome 22. We will then determine whether this junction fragment in the translocated unit is identical or varies in different chronic myelogenous leukemia patients and in any single patient whose disease progresses and/or who develops new chromosomal abnormalities. 3) Define the amplification unit for the myc oncogene in HL60 cells. HL60 is a human leukemic cell line which contains an amplified myc oncogene. When the cells are induced to differentiate to more mature granulocytes, there is markedly decreased myc expression. We will examine the relationship among myc expression, differentiation, and resistance to chemotherapeutic agents in ML60 cells. 4) We will use other available oncogene probes to examine cellular DNA and RNA from patients with other leukemias and lymphomas for changes in human oncogene organization and/or expression. These studies may provide new insights into the relationship between human oncogene organization and expression, and the origin of human malignancies in a manner analogous to recent reports implicating such changes in causing tumors in animals and transformation of tissue culture cells.