IDENTIFICATION OF TARGETS OF BCR ABL IN THE LEUKEMOGENIC

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DESCRIPTION: (Adapted from the investigator's abstract) Our long-term goal is to understand the molecular mechanism by which the bcr-abl oncogene acts in the pathogenesis of chronic myelogenous leukemia (CML). During the previous project period, we have successfully established a mouse CML model where Bcr-Abl efficiently induces a myeloproliferative disease resembling the chronic phase of human CML. We have used this murine CML model to define the roles of domains of Bcr-Abl and of specific signaling events in leukemogenesis. The mouse CML model has also provided a way to study the role played in leukemogenesis by extracellular factors produced by Bcr-Abl target cells, and by the altered interaction of these target cells with the in vivo microenvironment. Since Bcr-Abl alone induces only a myeloproliferative disorder, we recently sought to study the blast transformation of CML by testing if Bcr-Abl and the AML1/MDS1/EVI1 (AME) fusion protein cooperate to efficiently induce acute myelogenous leukemia. AME is a product of the human t(3;21)(q26;q22) translocation found as a secondary mutation in some cases of CML during the blast phase, and in therapy-related myelodysplasia and acute myelogenous leukemia. We found that while AME alone induces an acute myelogenous leukemia with a long latency (5 to 13 mounts), coexpression of Bcr-Able and AME induces a myeloproliferative disorder with accumulation of a large number of immature myeloid cells, resembling the accelerated or myeloid blast phase of CML, with a latency of 1 to 3 months. Building on our progress in several areas and our expertise with in vivo models of leukemia, this proposal aims to understand in greater depth and detail the roles of domains of Bcr-Abl of intracellular signaling events and of extracellular factors affected by Bcr-Abl in the pathogenesis of CML. In addition, this project will begin a detailed examination of the specific role of secondary mutations in the blast transformation of CML. Our specific aims for the project are as follows: 1) To test hypotheses regarding the roles of domains of Bcr-Abl and signaling pathways in Bcr-Abl leukemogenesis. 2) To test the hypotheses that altered expression of cytokine and adhesion molecules plays a role in Bcr-Abl leukemogenesis. 3) To test hypotheses regarding the role of secondary mutations in the molecular mechanism of blastic transformation of CML. These studies will help to further design rational therapeutic interventions for CML and to understand the mechanisms involved in leukemogenesis in general.