DEK EFFECTS ON GROWTH OF HEMATOPOIETIC CELLS

描述：（改编自研究者摘要）编码 序列特异性DNA结合蛋白DEK是t（6：9）的靶点， 人急性非淋巴细胞白血病，并与不良的临床表现有关。 预后 这种易位产生了一种嵌合核蛋白， 包含几乎整个DEK蛋白融合到C末端的三分之二， 核孔蛋白可以。 DEK与长末端重复序列中的一个序列结合 (LTR)人类免疫缺陷病毒2型，是必不可少的 在T细胞和髓样细胞中的病毒LTR的有丝分裂原诱导的转录。 CAN是核孔复合体的一部分，参与核质 运输 目的：探讨DEK的正常功能和白血病的发生机制。 DEK-CAN的潜力，研究人员产生了DEK缺陷小鼠， 通过同源重组表达DEC-CAN的小鼠。 初步结果 显示Dek -/-小鼠对病毒表现出增强免疫应答 感染并有髓系祖细胞数量增加，这表明 DEK在细胞增殖中的调节作用。 表达DEK-CAN的小鼠 不会自发地发生白血病，这表明额外的突变是 才能导致恶性肿瘤 研究人员假设DEK-CAN的作用是 作为一种改变的转录因子， DEK靶基因，导致异常造血反应， 最终是白血病 在这个项目中，研究人员将定义 DEK的转录特性，并评估这些特性如何受到影响 由DEK融合到CAN。 这也将涉及表型互补 分析具有突变DEK基因的DEK缺陷小鼠，以确定 DEK的结构域对其在体内的功能是必需的， 可以挽救DEK的损失 此外，调查人员将确定 DEK和DEK-CAN靶基因。 体内致白血病 DEK-CAN的潜力将通过测试其加速能力来确定 在倾向于发展白血病的小鼠中的白血病发生。 调查人员 指出这些研究将为正常情况提供有价值的见解 功能，并生成有关DEK-CAN如何 会导致白血病

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.