Investigating the role of retrotransposons in hematopoietic neoplasias.

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DESCRIPTION (provided by applicant): Investigating the role of retrotransposons in hematopoietic neoplasias. This proposal describes a five-year training program for development of an academic career in the genetic basis of hematologic malignancies. I am a physician-scientist, having completed doctoral studies in genetics with a focus on reproductive biology and in vivo tumor modifiers at Baylor College of Medicine as part of the combined M.D., Ph.D. program. I have also completed a residency in clinical pathology/laboratory medicine at Johns Hopkins Hospital where I am currently a clinical hematopathology fellow. I will complete this clinical fellowship in July 2008. I will establish myself as an independent investigator during this award period by developing my postdoctoral research and involving institutional strengths of the Johns Hopkins University School of Medicine. Many outstanding individuals and resources will contribute to a special environment for promoting the success of my research and career development. This effort will specifically involve collaborators within my primary department, the Department of Pathology, and co-mentorship from the Civin laboratory in the Cancer Center and the Boeke laboratory in the High Throughput Biology Center. The career development plan will build on my strong background in classical genetics, adding didactic training and primary research experiences in the forefront of modern genomics. The proposed work will focus on analysis of primary patient samples, which is outside my prior experience and will better position me to perform future studies with translational potential. My research will focus on: (i.) understanding the epigenetics of repetitive element stabilization in hematopoietic malignancies, and (ii.) applying a retrotransposon mapping strategy that I developed during my residency to investigate how these mobile elements contribute to oncogenesis and tumor progression. Insertional mutations caused by LINE repeat transposition are known causes of both heritable disease and somatic mutation in cancer. However, the extent of transposon participation in cancer development is not appreciated because genome-wide mapping strategies have not been available until now. This project is both very innovative and feasible, with potential to add an important dimension to our appreciation of tumor biology. Moreover, if LINE instability contributes meaningfully to cancer recurrence and resistance to therapeutics, this knowledge might be translated to application of antiretroviral therapies in cancer patients.