Mechanism of EVI1-induced Leukemogenesis

描述（由申请人提供）：Evil是一种锌指基因，在造血中起调节作用，在髓系白血病中起致病作用。我们和其他人已经表明，邪恶的影响细胞增殖，凋亡，分化和TGF？发信号。使用两种不同的测定，我们已经表明，EVI 1转化细胞的能力是严格依赖于其以序列特异性方式结合到DMA的GACAAGATA样基序的能力。这些发现意味着EVI 1与基因组中特定的高亲和力位点结合，并通过这种结合调节一组对其在白血病发生中的作用至关重要的关键靶基因。在使用几种互补细胞培养系统的一系列实验中，我们已经确定了其中的一些目标。它们包括参与控制造血（Gata 2，Zfpm 2/Fog 2），细胞凋亡（Bcl 2a 1b，Dapk 2），细胞周期（Ccnd 2）和TGF？信号（Skil）。我们假设EVI 1通过激活细胞增殖和细胞存活途径诱导白血病，并且这些效应通过Gata 2介导，Gata 2是EVI 1的关键下游靶点和造血的关键调节因子。为了解决这一假设，我们提出了三个具体目标。

DESCRIPTION (provided by applicant): Evil is a zinc finger gene that plays a regulatory role in hematopoiesis and a causative role in myeloid leukemia. We and others have shown that Evil has affects on cell proliferation, apoptosis, differentiation, and TGF? signaling. Using two different assays, we have shown that the ability of EVI1 to transform cells is strictly dependent on its ability to bind to DMA in a sequence-specific manner to a GACAAGATA-like motif. These findings imply that EVI1 binds to specific high-affinity sites in the genome and through this binding regulates a key set of target genes that are critical to its role in leukemogenesis. In a series of experiments using several complementary cell culture systems, we have identified some of these targets. They include genes involved in control of hematopoiesis (Gata2, Zfpm2/Fog2), apoptosis (Bcl2a1b, Dapk2), cell cycle (Ccnd2), and TGF? signaling (Skil). We hypothesize that EVI1 induces leukemia through the activation of cell proliferation and cell survival pathways, and that these effects are mediated through Gata2, a key downstream target of EVI1 and a critical regulator of hematopoiesis. To address this hypothesis, we propose three specific aims.