NOVEL GENE REARRANGED WITH BAR-ALPHA LOCUS IN CANCER

最近，一些人类癌症的病因学被认为与 随着染色体易位导致新的融合的形成 蛋白质。在这些融合中，有嵌合的转录调控因子。 最近发现了PML基因和RARpha基因之间的融合 是与急性早幼粒细胞白血病相关的t(15；17)的结果 白血病(APL)。PML-RAR融合蛋白具有不同的转录水平 与RARpha相比的效应及其转录效应 野生型PML蛋白仍未完全确定。它是 目前认为，对世界银行的职能 野生型和融合PML蛋白可能会对 急性早幼粒细胞白血病的病因。在寻找RARpha的新的重排中 APL患者我们分离到一种新的易位基因 1例APL患者和1例t(11；17)患者的RARpha基因座。新基因 编码一个含有9个锌指结构域的蛋白质，并将 转录调控蛋白大家族中的蛋白质与 果蝇蛋白Kruppel以及大量的人类 转录因子包括WT-1肿瘤抑制蛋白。在……里面 与PML相反，PML在所有造血系中都有表达 经过检测，我们将这个新基因命名为PLZF(早幼粒细胞白血病 锌指)，主要在髓系中表达。PLZF是 以阶段特异的方式表达，在髓系细胞中下调 骨髓细胞中存在的对维甲酸反应的谱系 外周血粒细胞中不存在前体细胞。在本建议书中 我们将完成PLZF基因和融合cDNA的克隆 将PLZF和RARAlpha联系起来。有了这些试剂，我们进一步 PLZF基因和蛋白表达模式的研究 在正常造血和急性白血病中。我们将分离出 包含顺式作用元件的基因组片段 控制PLZF的表达。我们将确定DNA结合和 PLZF蛋白转录效应活性的研究 这些基因可能是PLZF蛋白的靶标。我们将比较和 比较野生型的转录和DNA结合活性 PLZF蛋白和PLZF-RARpha融合蛋白，以确定 它们在我们的指征患者的病因中可能起到了什么作用 疾病。我们将确定是否有其他APL或其他患者 各种类型的急性髓系白血病均有PLZF/RAR异常。 总而言之，这些研究将对髓系谱系产生新的见解 特异性基因，其在正常粒细胞生成中的作用及其在 急性白血病的病因学。同时，我们将了解更多关于 维甲酸及其受体在病理和治疗中的作用 白血病的症状。

Recently the etiology of a number of human cancers has been associated with chromosomal translocations leading to the formation of novel fusion proteins. Amongst these fusions are chimeric transcriptional regulators. Recently, the fusion between the PML gene and the RARalpha gene was found to be the result of the t(15; 17) associated with acute promyelocytic leukemia (APL). The PML-RAR fusion protein has different transcriptional effects compared to RARalpha and its transcriptional effect compared to the wild-type PML protein remains incompletely characterized. It is currently believed that an understanding of the functions of the wild-type and fusion PML proteins may yield new insights into the etiology of APL. In a search for novel rearrangements of the RARalpha in patients with APL we have isolated a new gene translocated to the RARalpha locus in a patients with APL and a t(11; 17). The novel gene encodes a protein containing 9 zinc fingers domains and places the protein in a large family of transcriptional regulators related to the Drosophila protein Kruppel as well as a large number of human transcription factors including the WT-1 tumor suppressor protein. In contrast to PML, which is expressed in all hematopoietic lineages examined, the novel gene, we have termed PLZF (Promyelocytic Leukemia Zinc Finger), is expressed predominantly in the myeloid lineage. PLZF is expressed in a stage specific manner, down regulated in myeloid cell lines in response to retinoic acid, present in bone marrow myeloid precursors but absent in peripheral blood granulocytes. In this proposal we will complete the cloning of the PLZF gene and the fusion cDNAs linking PLZF and the RARalpha. With these reagents in hand we further our studies into the pattern of expression of the PLZF gene and protein in normal hematopoiesis and in acute leukemia. We will isolate the genomic fragment containing the cis-acting elements involved in the control of PLZF expression. We will determine the DNA binding and transcriptional effector activity of the PLZF protein and search for genes which may be the target of the PLZF protein. We will compare and contrast the transcriptional and DNA binding activity of the wild-type PLZF protein and PLZF-RARalpha fusion proteins, in order to determine what role they may have had in the etiology of our index patient's disease. We will determine whether other patients with APL or other forms of acute myeloid leukemia have PLZF/RAR abnormalities. Collectively these studies will yield new insight into a myeloid lineage specific gene, its role in normal granulocytopoiesis and possible role in the etiology of acute leukemia. At the same time we will learn more of the role of retinoic acid and its receptor in the pathology and treatment of leukemia.