Activation of cellular proto-oncogenes as a result of chromosomal abnormalities has been implicated in the development of some human malignancies. Perhaps one of the most striking examples of this association occurs in chronic myelogenous leukaemia, where the Philadelphia (Ph) translocation results in substitution of the 5' end of the c-abl proto-oncogene with bcr gene sequences. A unique hybrid bcr-abl message is produced. As the Ph translocation is also present in some patients with acute lymphoblastic leukaemia, we initiated studies to determine if similar genomic events occur in these two different forms of Ph-positive leukaemia. Here we report that the Ph translocation in acute lymphoblastic leukaemia can result in production of a novel aberrant c-abl protein that is distinct from the bcr-abl protein found in Ph-positive chronic myelogenous leukaemia. Our observations suggest that alternative mechanisms of activation of c-abl exist, and may be important in the development of human acute lymphoid rather than chronic myeloid malignancies.