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Research Abstracts Online
January 2009 - March 2010

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University of Minnesota Twin Cities
College of Biological Sciences
Medical School
Department of Genetics, Cell Biology, and Development

PI: David A. Largaespada

Analysis of Insertion Mutations and Gene Expression Patterns in Cancer

These researchers are working to exploit insertional mutagenesis for cancer gene discovery and functional genomics in the mouse. The group has heavily invested in the use of a vertebrate-active transposon system, called Sleeping Beauty (SB), for insertional mutagenesis in mouse somatic and germline cells. The human cancer genome project promises to help reveal the typical landscape of genomic changes in human cancer, but it must be supplemented with complementary large-scale approaches for functional validation of targets and genetic screens that can identify cancer gene candidates. The Largaespada laboratory has developed approaches, using the SB transposon system, which can meet these needs. They have shown that SB transposon vectors can be mobilized in the soma of transgenic mice allowing forward genetic screens for cancer genes involved in sarcoma and lymphoma/leukemia to be performed in living mice. Analysis, mapping, and annotation of hundreds of thousands of transposon insertion site sequences require MSI resources. The system has now been altered so that tissue-specific transposon mutagenesis for cancer gene discovery in various organs can be accomplished.

The group is also using mouse models of murine leukemia virus-induced acute myeloid leukemia (AML) to identify and characterize genes that have a role in leukemia progression after disease is initiated by mutations relevant to human AML. This work also includes genetic studies of myeloid leukemia chemotherapy resistance and relapse. AML is the most common adult leukemia. The lab is exploring these questions by using MuLV mutagenesis in mice carrying specific human translocation fusion oncogenes known to play a role in human AML.

Group Members

Vincent Keng, Research Associate
Jon Larson, Graduate Student
Sue Rathe, Graduate Student
Tim Starr, Research Associate