Mechanism of EVI1-induced Leukemogenesis

描述（申请人提供）：Evil是一种锌指基因，在造血过程中起调节作用，在髓性白血病中起致病作用。我们和其他人已经证明Evil对细胞增殖、凋亡、分化和TGF？信号。通过两种不同的实验，我们已经证明EVI1转化细胞的能力严格依赖于它以序列特异性方式与DMA结合到gacaagata样基序的能力。这些发现表明，EVI1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关键的靶基因，这些靶基因对其在白血病发生中的作用至关重要。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一些目标。它们包括参与控制造血（Gata2, Zfpm2/Fog2），细胞凋亡（Bcl2a1b, Dapk2），细胞周期（Ccnd2）和TGF？信号(斯基尔)。我们假设EVI1通过激活细胞增殖和细胞存活途径诱导白血病，而这些作用是通过gatta2介导的，gatta2是EVI1的关键下游靶点，也是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.