STAT ACTIVATION IN LEUKEMIAS

描述：(申请人摘要)这个项目的第一个目的是 了解导致结构性激活的分子机制 Janus激酶(JAK)/信号转导和转录激活因子 急性髓系白血病部分病例的(STAT)信号转导通路 急性淋巴细胞白血病(AML)、急性淋巴细胞白血病(ALL)和慢性粒细胞白血病 (CML)。这个项目的第二个目的是确定 结构型JAK2/STAT5在细胞的发育和维持中的激活 体外和体内的白血病表型。主要的假设是 测试的是导致结构性突变的特定激活突变 JAK/STAT信号转导通路的激活负责 发展和/或维持白血病细胞的生存和增殖，以及 在表达组成性激活的STAT5的白血病细胞中，抑制 STAT5的激活或功能。提出了三个具体的目标来测试这些 假设。具体目的1是确定本构关系的机理(S) 人白血病细胞系HEL/Dami和Meg-01的活化具体目标2 是确定结构性JAK/STAT信号通路是否被激活 在维持原发白血病表型中起重要作用 人类急性髓系白血病细胞。具体目标3是确定双链的能力 含有STAT5结合域的“诱骗”寡核苷酸可抑制 白血病细胞在体内不受调控的存活和增殖。要将模型 待检测内容包括：(1)人HEL/Dami和Meg-01细胞株移植于 亚致死剂量照射的NOD/SCID小鼠；(2)BCR/ABL转基因小鼠， 当小鼠饮用的四环素被剥夺时，它们会患上白血病 水(来自丹·特宁)；(3)骨髓移植小鼠 转染TEL/JAK2或TEL/ABL逆转录病毒的细胞，导致 具有结构性激活的STAT5的白血病的发展。这些 研究应该导致对白血病治疗的新的理解方法 其中STAT激活在维持白血病表型中起作用。

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.