STAT ACTIVATION IN LEUKEMIAS

白血病中的 STAT 激活

• 批准号: 6262514
• 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/6262514
• 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.

说明：（申请人摘要）本项目的第一个目的是 了解负责组成性激活的分子机制 Janus激酶（JAK）/信号转导和转录激活因子 STAT信号转导通路在某些急性髓细胞白血病中的作用 (AML)急性淋巴细胞白血病（ALL）和慢性髓细胞白血病 （CML）。本项目的第二个目的是确定以下方面的重要性： JAK 2/STAT 5组成性激活在发育和维持中的作用 白血病表型，在体外和体内。主要假设是 测试的是导致组成性 JAK/STAT信号转导通路的激活负责 发展和/或维持白血病细胞存活和增殖，和 在表达组成性激活的STAT 5的白血病细胞中， STAT 5的激活或功能。提出了三个具体目标来测试这些 假设具体目标1是确定本构的机制。 在HEL/Dami和Meg-01人白血病细胞系中的活化。具体目标2 是为了确定组成性JAK/STAT信号通路激活是否 在维持原发性白血病表型中起重要作用。 人AML细胞。具体目标3是确定双链 含有STAT 5结合结构域的“诱饵”寡核苷酸，以抑制STAT 5结合结构域。 白血病细胞在体内的不受调节的存活和增殖。模特们 （1）将人HEL/Dami和Meg-01细胞系植入 亚致死照射的NOD/SCID小鼠;（2）tet-off bcr/abl转基因小鼠， 当老鼠的饮水中没有四环素时， 水（从DanTenen获得）;和（3）移植骨髓的小鼠 用TEL/JAK 2或TEL/ABL逆转录病毒转染的细胞，其导致 具有组成性激活的STAT 5的白血病的发展。这些 这些研究将为白血病的治疗带来新的认识 其中STAT活化在维持白血病表型中起作用。