In leukemic cells of over 95% of patients with chronic myelogenous leukemia (CML), 20-25% of adult acute lymphoblastic leukemia (ALL) and 2-5% of pediatric ALL, the c-abl proto-oncogene undergoes a t(9;22) chromosomal translocation producing the Philadelphia (Ph') chromosome. This results in the fusion of c-abl sequences to the phl gene of chromosome 22 and the activation of the c-abl protein- tyrosine kinase. In the past, detection of the Ph' translocation has been dependent upon karyotype analysis. A more accurate DNA probe test for Ph+ CML has been developed at Oncogene Science, Inc. There remain several limitations with this test however, including its inability to detect many of the c-abl translocations in ALL. The primary objectives of this application are to format rapid immunologic tests for the diagnosis of Ph+ CML and Ph+ ALL, and to develop methods to quantitate leukemic cells in blood and bone marrow. Antibodies directed against different domains of the c- abl fusion proteins will be paired in antigen capture (sandwich) assays. We will also evaluate the application of histopathology to detect the activated c-abl kinase in Ph+ leukemic cells, via the generation of antibodies which recognize specifically the phosphotyrosyl-form of the abl kinase.
