NOVEL GENE REARRANGED WITH BAR-ALPHA LOCUS IN CANCER

最近，许多人类癌症的病因学已经与 染色体易位导致新融合体的形成 proteins. 在这些融合体中有嵌合转录调节因子。 最近，发现PML基因和RAR α基因之间的融合 t（15; 17）与急性早幼粒细胞白血病相关 白血病（APL）。 PML-RAR融合蛋白具有不同的转录水平， 与RAR α相比，其转录作用与 野生型PML蛋白的特征仍然不完全。 是 目前认为，了解的职能， 野生型和融合PML蛋白可能会产生新的见解 APL的病因 为了寻找新的RAR α重排， 在APL患者中，我们已经分离出一种新的基因， t（11; 17）的APL患者的RAR α基因座。新基因 编码含有9个锌指结构域的蛋白质， 一个转录调节因子大家族中的蛋白质， 果蝇蛋白Kruppel以及大量人类 转录因子，包括WT-1肿瘤抑制蛋白。 在 与在所有造血谱系中表达的PML相反 我们检查了这种新基因，我们称之为PLZF（早幼粒细胞白血病 锌指蛋白）主要在髓系中表达。 PLZF是 以阶段特异性方式表达，在骨髓细胞中下调 对维甲酸有反应的细胞系，存在于骨髓髓样细胞中 前体细胞，但缺乏外周血粒细胞。 本提案中 我们将完成PLZF基因和融合cDNA的克隆 连接PLZF和RAR α。 有了这些试剂，我们进一步 我们对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。 我们将隔离 基因组片段包含参与的顺式作用元件， 控制PLZF表达。 我们将确定DNA结合， PLZF蛋白的转录效应子活性，并寻找 这些基因可能是PLZF蛋白的靶基因。 我们会比较， 对比野生型的转录和DNA结合活性， PLZF蛋白和PLZF-RAR α融合蛋白，以确定 它们在我们的索引患者的病因学中可能起什么作用， 疾病 我们将确定其他APL患者或其他 急性髓性白血病的形式具有PLZF/RAR异常。 总的来说，这些研究将对骨髓谱系产生新的认识。 特异性基因，其在正常粒细胞生成中作用以及在 急性白血病的病因 同时，我们将了解更多关于 维甲酸及其受体在视网膜病变中的作用及治疗 白血病

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.