STAT ACTIVATION IN LEUKEMIAS

白血病中的 STAT 激活

• 批准号: 6497570
• 负责人: Kenneth S. Zuckerman
• 金额: $ 24.51万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6497570
• 关键词: JAK kinase; NOD mouse; Retroviridae; SCID mouse; acute lymphocytic leukemia; acute myelogenous leukemia; carcinogenesis; chronic myelogenous leukemia; clinical research; enzyme activity; enzyme inhibitors; gene mutation; genetically modified animals; growth factor receptors; human subject; neoplasm /cancer genetics; oligonucleotides; protein tyrosine phosphatase; transcription factor; transfection /expression vector

DESCRIPTION: (Applicant's Abstract) The first purpose of this project is to understand the molecular mechanisms responsible for the constitutive activation of the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signal transduction pathways in some cases of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myelogenous leukemia (CML). The second purpose of this project is to determine the importance of constitutive JAK2/STAT5 activation in development and maintenance of the leukemic phenotype, both in vitro and in vivo. The primary hypotheses being tested are that specific activating mutations that lead to constitutive activation of JAK/STAT signal transduction pathways are responsible for the development and/or maintenance of leukemic cell survival and proliferation, and that, in leukemic cells expressing constitutively activated STAT5, inhibition of STAT5 activation or function. Three specific aims are proposed to test these hypotheses. Specific Aim 1 is to determine the mechanism(s) of constitutive activation in the HEL/Dami and Meg-01 human leukemic cell lines. Specific Aim 2 is to determine whether constitutive JAK/STAT signaling pathway activation plays an important role in maintenance of the leukemic phenotype of primary human AML cells. Specific Aim 3 is to determine the ability of double-stranded "decoy" oligonucleotides containing the STAT5 binding domain to inhibit the unregulated survival and proliferation of leukemic cells in vivo. The models to be tested include: (1) human HEL/Dami and Meg-01 cell lines implanted in sublethally irradiated NOD/SCID mice; (2) tet-off bcr/abl transgenic mice, which develop leukemia when mice are deprived of tetracycline in their drinking water (obtained from Dan Tenen); and (3) mice transplanted with bone marrow cells transfected with TEL/JAK2 or TEL/ABL retroviruses, which result in development of leukemias that have constitutively activated STAT5. These studies should lead to new understanding approaches for treatment of leukemias in which STAT activation plays a role in maintenance of the leukemic phenotype.

描述：（申请人的摘要）该项目的第一个目的是 了解负责本构激活的分子机制 Janus激酶（JAK）/信号换能器和转录激活因子 （STAT）在某些急性髓样白血病的情况下，信号转导途径 （AML），急性淋巴细胞白血病（ALL）和慢性骨髓性白血病 （CML）。该项目的第二个目的是确定 构成JAK2/STAT5在开发和维护中激活 体外和体内的白血病表型。主要假设是 经过测试的是导致本构的特定激活突变 JAK/STAT信号转导途径的激活负责 营养和/或维持白血病细胞的生存和增殖，以及 在表达组成型激活STAT5的白血病细胞中，抑制作用 STAT5激活或功能。提出了三个特定目标来测试这些 假设。具体目的1是确定本构的机制 HEL/DAMI和MEG-01人类白血病细胞系中的激活。具体目标2 是确定构成型jak/stat信号通路是否激活 在维持主要的白血病表型中起着重要作用 人AML细胞。特定目标3是确定双链的能力 “诱饵”含有STAT5结合结构域的寡核苷酸抑制 体内白血病细胞的生存和增殖。模型 被测试包括：（1）植入的人类HEL/DAMI和MEG-01细胞系 共辐射的点头/SCID小鼠； （2）Tet-off BCR/ABL转基因小鼠， 当小鼠饮酒中剥夺了四环素时，会出现白血病 水（从Dan Tenen获得）； （3）用骨髓移植的小鼠 用TEL/JAK2或TEL/ABL逆转录病毒转染的细胞，这导致 构成活化的STAT5的白血病的发展。这些 研究应导致新的理解白血病方法 其中统计激活在维持白血病表型中起作用。