DEK EFFECTS ON GROWTH OF HEMATOPOIETIC CELLS

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DESCRIPTION: (Adapted from investigator's abstract) The gene encoding the sequence specific DNA binding protein DEK is the target of t(6:9) found in human acute nonlymphocytic leukemia, and is associated with a poor clinical prognosis. This translocation creates a chimeric nuclear protein that contains almost the entire DEK protein fused to the C-terminal two thirds of the nucleoporin CAN. DEK binds to a sequence in the long terminal repeat (LTR) of human immunodeficiency virus type 2 and is essential for mitogen-induced transcription of the viral LTR in T cells and myeloid cells. CAN, part of the nuclear pore complex, is involved in nucleocytoplasmic transport. To investigate the normal function of DEK and the leukemogenic potential of DEK-CAN, the investigators generated DEK-deficient mice and DEC-CAN expressing mice by homologous recombination. Preliminary results show that Dek -/- mice exhibit an enhanced immune response upon viral infection and have elevated numbers of myeloid progenitors, suggesting a regulatory role for DEK in cell proliferation. DEK-CAN-expressing mice do not spontaneously develop leukemia, indicating that additional mutations are needed to cause malignancy. The investigators hypothesize that DEK-CAN acts as an altered transcription factor that interferes with the expression of DEK target genes, resulting in abnormal hematopoietic responses and eventually leukemia. In this project, the investigators will define the transcription properties of DEK and assess how these properties are affected by DEK s fusion to CAN. This will also involve phenotypic complementation analysis of DEK-deficient mice with mutant DEK genes, to determine which domains of DEK are essential for its function in vivo, and whether DEK-CAN can rescue the loss of DEK. In addition, the investigators will identify DEK and DEK-CAN target genes by using cDNA RDA. The in vivo leukemogenic potential of DEK-CAN will be determined by testing its ability to accelerate leukemogenesis in mice predisposed to develop leukemia. The investigators state that these studies will provide valuable insights into the normal functions of DEK and generate important information on how DEK-CAN contributes to leukemogenesis.