STAT ACTIVATION IN LEUKEMIAS

白血病中的 STAT 激活

• 批准号: 6848790
• 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 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6848790
• 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：（申请人摘要）该项目的首要目的是 了解负责组成型激活的分子机制 Janus 激酶 (JAK)/信号转导子和转录激活子 急性髓系白血病部分病例中的（STAT）信号转导通路 (AML)、急性淋巴细胞白血病 (ALL) 和慢性粒细胞白血病 （慢性粒细胞白血病）。该项目的第二个目的是确定 JAK2/STAT5 的组成型激活在发育和维持中 白血病表型，体外和体内。主要假设是 测试的是导致组成型的特定激活突变 JAK/STAT 信号转导通路的激活负责 白血病细胞存活和增殖的发展和/或维持，以及 在表达组成型激活的 STAT5 的白血病细胞中，抑制 STAT5 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 是确定组成机制 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JAK/STAT信号通路是否组成型激活 在原发性白血病表型的维持中起重要作用 人类 AML 细胞。具体目标3是确定双链的能力 含有 STAT5 结合域的“诱饵”寡核苷酸可抑制 体内白血病细胞的存活和增殖不受控制。模型到 待测试的包括：（1）植入人HEL/Dami和Meg-01细胞系 亚致死照射的 NOD/SCID 小鼠； (2) tet-off bcr/abl 转基因小鼠， 当小鼠的饮酒中没有四环素时，就会患上白血病 水（从 Dan Tenen 获得）； (3) 骨髓移植小鼠 用 TEL/JAK2 或 TEL/ABL 逆转录病毒转染细胞，从而产生 STAT5 持续激活的白血病的发展。这些 研究应带来治疗白血病的新方法 其中 STAT 激活在白血病表型的维持中发挥作用。