The Philadelphia chromosome-positive human leukemias, including the myeloproliferative syndrome chronic myelogenous leukemia (CML), and acute lymphoid and myeloid leukemias, constitute an important group of hematologic neoplasms whose clinical behavior has been very well characterized. As the product of the Philadelphia chromosome, activated bcr/abl fusion genes have been implicated in the pathogenesis of the Philadelphia-positive leukemias, but the way in which these abnormal genes induce leukemia is unknown. The long-term objective of this proposal is to gain an understanding of the cellular and molecular mechanism of leukemogenesis by bcr/abl genes by expression of these genes in the hematopoietic system of mice. The two major forms of bcr/abl will be expressed in the murine hematopoietic system by the use of retroviral gene transfer and transgenic mice. In the first Specific Aim, the target cells for the induction of specific hematological malignancies in mice by the P210(bcr/abl) gene will be defined. The multipotential cell which appears to be the target for the induction of a CML-like syndrome in mice by the P210(bcr/abl) gene will be characterized by lineage analysis in primary animals, by direct purification of target cells, and by the complementary method of expression of bcr/abl in transgenic mice. In the second Aim, the difference in disease spectrum induced by the P210(bcr/abl) gene and the P190(bcr/abl) gene will be carefully defined using a similar strategy. The determinants in bcr which allow the induction of a myeloproliferative syndrome as opposed to acute leukemia will be identified by a deletion mapping approach. These experiments, which are difficult or impossible to carry out on humans, should clarify the mechanism of leukemogenesis by bcr/abl genes, offering insight into the pathogenesis of the human Philadelphia-positive leukemias and suggesting new therapeutic approaches to these diseases.
