Leukemogenesis by Murine Retroviruses

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DESCRIPTION (provided by applicant): Murine leukemia viruses (MuLVs) are potent inducers of hematopoietic tumors in mice. Transcriptional regulatory sequences within the long terminal repeats (LTRs) of these viruses control the expression of the viral genomes and play crucial roles in the process of tumorigenesis by these viruses. They determine the type of tumor that specific MuLVs cause, they influence the ability of the viruses to infect the target cells for disease, and they play a role in the tumorigenic activation of cellular genes following adjacent insertion of the viral genomes. Experiments are proposed here to compare the transcriptional capacity of different MuLVs on templates that are integrated at various sites in the mouse genome. These experiments will use cells from the lineages in which these viruses cause tumors. A second line of experiments is proposed to identify the cellular genes that are activated by these viruses in tumors and to begin to test how these genes participate in tumorigenesis. High-throughput technology is now available that allows such genetic screens to be performed far more rapidly than in the past. This approach will be applied to two separate MuLV tumor systems. The genes that are identified in these screens are expected to provide insight about important and perhaps unanticipated molecular mechanisms that contribute to the generation of leukemias and lymphomas.