Chromosome 9, band q34, the location of the proto-oncogene c-abl, is a frequent site of translocations in human myeloid and lymphoid leukemia. The best studied translocation at this locus is the exchange between chromosomes 9 and 22, or the t(9;22), which occurs in chronic myelogenous leukemia (CML). The goal is to study translocations which occur at this site in leukemias other than CML, using the t(i;22) of CML as a model, and the c-abl gene as a reference point.
Our aims are to combine methods of recombinant DNA technology (Southern hybridization, pulsed gel electrophoresis, and molecular cloning), with cytogenetic techniques (gene-localization by chromosomal in-situ hybridization) to analyze chromosomal translocations, and to use this data to clone the translocation break points and to better understand the disease process. Specifically: 1) To analyze a cell line derived from a T-cell leukemia with t(7;9), and to clone the rearranged T-cell receptor genes at the presumed breakpoint on chromosome 7; 2) To determine the location of breakpoints in a lymphoblastic leukemia cell line with t(9;22), so-called Philadelphia-positive acute lymphoblastic leukemia, and to attempt to clone the break points; 3) To analyze the chromosomal breakpoints in t(9;22) in 13 patients with acute lymphoblastic leukemia, to compare these to CML, and to define molecular and clinical subtypes of this disease; 4) To similarly study the t(6;9) in three patients with acute myeloid leukemia; 5) To use the results of these studies, and the DNA sequence obtained, to prepare a detailed map of the c-abl gene and its surrounding locus, using this information to enhance our understanding of the biology of these leukemias and their relationship to c-abl or to other genes that may be involved. These studies should provide a better understanding of the molecular basis of neoplastic transformation in leukemic cells, as well as provide new and interesting information about the detailed structure of c-abl and its chromosomal surroundings. Lastly, the application of these findings in patient samples will have clinically useful diagnostic and prognostic implications.
