DEK EFFECTS ON GROWTH OF HEMATOPOIETIC CELLS

描述：(改编自研究人员摘要)编码 序列特异性DNA结合蛋白dek是t(6：9)的靶标，在 人类急性非淋巴细胞白血病，临床表现不佳 预后。这种易位产生了一种嵌合核蛋白， 包含几乎整个DEK蛋白与C-末端融合三分之二 核孔素可以。DEK与长末端重复序列结合 (Ltr)是人类免疫缺陷病毒2型的重要组成部分。 有丝分裂原在T细胞和髓系细胞中诱导病毒LTR转录。 CaN是核孔复合体的一部分，与核质有关 运输。探讨DEK的正常功能与白血病的关系 DEK-CAN的潜力，研究人员产生了DEK缺陷小鼠和 通过同源重组在小鼠体内表达DEC-CAN。初步结果 显示DEK-/-小鼠对病毒的免疫反应增强 感染，髓系祖细胞数量增加，表明 DEK在细胞增殖中的调节作用。表达dek-can的小鼠做 不会自发地患白血病，这表明额外的突变是 才能引起恶性反应。调查人员假设德肯的行为 作为一种改变的转录因子，干扰基因的表达 DEK靶基因，导致异常的造血反应和 最终得了白血病。在这个项目中，调查人员将定义 DEK的转录特性并评估这些特性是如何受到影响的 由德克S融合为能。这也将涉及表型互补。 对带有突变dek基因的dek缺陷小鼠进行分析，以确定哪种 DEK的结构域对于其在体内的功能是必不可少的，以及DEK-Can 可以挽回德克的损失。此外，调查人员将确定 DEK和DEK-CAN利用cDNARDA靶向基因。体内白血病的发生 DEK-CAN的潜力将通过测试其加速能力来确定 易患白血病的小鼠的白血病发生。调查人员 声明这些研究将提供对正常情况的宝贵见解 功能，并生成有关dek-can的重要信息 有助于白血病的发生。

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.