): A career development award will provide the opportunity to obtain in depth training and experience in the essentials of cancer and hematology research. The proposed training involves didactic study, professional meetings, and collaborations with leaders in the fields of cancer and leukemia research. The goal of the research plan is to provide an opportunity to learn basic techniques in the study of cancer and malignant hematologic diseases, to learn to think creatively and analytically, and to develop the skills necessary to develop a successful independent research program. The combination of Dr. Robert A. Weinberg as a primary sponsor and Dr. George Q. Daley as a co-sponsor will provide outstanding mentorship. Dr. Weinberg has an established record of training outstanding investigators. Dr. Daley has a strong background in the study of human leukemias and as a clinical hematologist he provides an excellent role model of a physician-scientist. The educational opportunities and the resources that the Whitehead Institute for Biomedical Research provides are outstanding, and will complement the strong mentorship of Dr. Weinberg and Dr. Daley. The proposed research seeks to explain the clinical course of chronic myelogenous leukemia (CML). CML initially manifests as a clinically manageable chronic phase disease, characterized by a hyperproliferation of relatively normal cells. CML inevitably progresses to blast phase, a virtually u n t reatable acute leukemia. The genetic changes responsible for the progression to blast are unknown. The Weinberg laboratory has recently developed a model for cooperating oncogenes in human cells, demonstrating that primary human cells can be transformed by the combination of a viral oncogene, a ras oncogene, and the t e l o merase gene. This experimental system yields a model of human carcinogenesis that can be used to formulate a number of specific, testable hypotheses that may explain the progression of chronic phase CML to blast phase. Building on the observation that human chronic phase and blast phase cells engraft differently in the immunocompromised NOD/SCID mouse, hypotheses regarding the progression of chronic phase CML can be tested in vivo. The first two parts of the research address the role of telomerase in the natural history of CML. The second two parts explore the role of oncogenes in the pathogenesis of blast phase CML and attempt to build a multi-step model to explain the progression of chronic phase CML to blast phase.
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