Mechanism of EVI1-induced Leukemogenesis

EVI1诱导白血病发生的机制

• 批准号: 8109836
• 负责人: Archibald S. Perkins
• 金额: $ 26.08万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-13 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8109836
• 关键词: Address; Affect; Affinity; Apoptosis; Apoptotic; Binding; Biochemical; Biological Assay; Bone Marrow Cells; Cell Culture System; Cell Cycle; Cell Line; Cell Proliferation; Cell Survival; Collaborations; Complex; Data; EVI1 gene; Gene Targeting; Genes; Genetic Transcription; Genome; Genomics; Growth; Hematopoiesis; Hypersensitivity; Insertional Activations; Interferons; Knock-out; Leukemic Cell; Marrow; Mediating; Microarray Analysis; Mus; Myeloid Leukemia; Nucleic Acid Regulatory Sequences; Pathway interactions; Phenotype; Play; Protein Isoforms; Relative (related person); Reporting; Research Personnel; Role; Series; Signal Transduction; Site; Specificity; Testing; Transcriptional Activation; Transcriptional Regulation; Transgenes; Universities; Up-Regulation; Wisconsin; Zinc Fingers; base; cell growth; cell transformation; chromatin immunoprecipitation; immortalized cell; insight; leukemia; leukemogenesis; programs; research study; retroviral transduction; transcription factor

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.

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。

项目成果

Essential role of PR-domain protein MDS1-EVI1 in MLL-AF9 leukemia.

• DOI: 10.1182/blood-2012-08-453662
• 发表时间: 2013-10
• 期刊: Blood
• 影响因子: 20.3
• 作者: Yi Zhang;Kristin S. Owens;Layla Hatem;C. Glass;Kannan Karuppaiah;F. Camargo;A. Perkins

Global Identification of EVI1 Target Genes in Acute Myeloid Leukemia.

• DOI: 10.1371/journal.pone.0067134
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Glass C;Wuertzer C;Cui X;Bi Y;Davuluri R;Xiao YY;Wilson M;Owens K;Zhang Y;Perkins A
• 通讯作者: Perkins A