BCR-ABL TARGET IDENTIFICATION IN THE LEUKEMOGENIC

白血病中的 BCR-ABL 靶标识别

• 批准号: 2668016
• 负责人: Ruibao Ren
• 金额: $ 28.37万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-07 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2668016
• 关键词: binding proteins; carcinogenesis; chronic myelogenous leukemia; enzyme activity; intermolecular interaction; laboratory mouse; molecular cloning; neoplasm /cancer genetics; neoplastic transformation; oncogenes; phosphorylation; protein tyrosine kinase; tissue /cell culture

DESCRIPTION: (adapted from the investigator's abstract) The broad objective is to elucidate the molecular mechanism by which the bcr-abl oncogene acts in the pathogenesis of chronic myelogenous leukemia (CML). The bcr-abl oncogene is created by a chromosomal translocation, which fuses a portion of the breakpoint cluster region (bcr) gene and most of the abl gene. The project focuses on the interaction of Bcr-Abl with other proteins. The Abl tyrosine kinase activity in Bcr-Abl is required for the neoplastic transformation, indicating that Abl induces leukemia through phosphorylation of target proteins. Dr. Ren's preliminary data indicate that Abl recruits specific substrates via protein-protein interactions mediated by its non-catalytic domains. Dr. Ren has shown that coexpression of Bcr-Abl and the Abl-binding protein (ABP) Grb2 induces a CML-like disease in mice. Therefore, he hypothesizes that the ABPs play important roles in regulating and mediating the oncogenic functions of Abl. In this project, he will further identify ABPs from the leukemic cells, and investigate the effect of the protein-protein interactions on the oncogenic function of Bcr-Abl. The long-term objectives are to determine whether the oncogenic function of Bcr-Abl is regulated and/or mediated by its binding proteins, and if so, whether the malignant potential of Bcr-Abl can be mitigated by controlling these interactions. Such information will help to elucidate the leukemogenic pathway activated by Bcr-Abl and help to develop therapeutic drugs for human leukemia. Accordingly, the specific aims of the project are as follows: (1) To test the hypothesis that the association of Grb2 or other ABPs with Bcr-Abl is required for the transformation of Bcr-Abl via examining the effect of the mutations in Bcr-Abl that interrupt ABP- binding on neoplastic transformation; (2) To test the hypothesis that cells of hematopoietic lineage derived from CML patients contain a unique set of ABPs by identifying the potential targets of Bcr-Abl from CML cells; (3) To test the hypothesis that the malignant potential of Bcr-Abl can be mitigated by interrupting the interaction between Bcr-Abl and ABPs in trans by examining the ability of overexpression of ABPs or their mutant polypeptides to block cellular transformation.

描述：（改编自研究者的摘要）广泛 目的是阐明 bcr-abl 的分子机制 癌基因在慢性粒细胞白血病 (CML) 的发病机制中发挥作用。 bcr-abl癌基因是由染色体易位产生的， 融合了断点簇区域（bcr）基因的一部分和大部分 abl基因。该项目重点研究 Bcr-Abl 与 其他蛋白质。 Bcr-Abl 中的 Abl 酪氨酸激酶活性是必需的 对于肿瘤转化，表明 Abl 诱导白血病 通过靶蛋白的磷酸化。任博士的初步数据 表明 Abl 通过蛋白质-蛋白质招募特定底物 由其非催化域介导的相互作用。任博士已经表明 Bcr-Abl 和 Abl 结合蛋白 (ABP) Grb2 的共表达 在小鼠中诱发类似 CML 的疾病。因此，他假设 ABP 在调节和介导致癌方面发挥着重要作用 Abl 的功能在这个项目中，他将进一步识别来自 白血病细胞，并研究蛋白质-蛋白质的作用 Bcr-Abl 致癌功能的相互作用。长期来看 目的是确定 Bcr-Abl 是否具有致癌功能 是由其结合蛋白调节和/或介导的，如果是这样，是否 Bcr-Abl 的恶性潜力可以通过控制这些来减轻 互动。这些信息将有助于阐明白血病的致病基因 Bcr-Abl 激活途径有助于开发治疗药物 人类白血病。因此，该项目的具体目标是 如下： (1) 检验 Grb2 或 Grb2 关联的假设 Bcr-Abl 的转化需要其他带有 Bcr-Abl 的 ABP 通过检查 Bcr-Abl 突变的影响来中断 ABP- 与肿瘤转化有关； (2) 检验假设 来自 CML 患者的造血谱系细胞含有 通过识别 Bcr-Abl 的潜在靶标，获得一组独特的 ABP 慢性粒细胞白血病细胞； (3) 检验以下假设： 通过中断 Bcr-Abl 之间的相互作用可以减轻 Bcr-Abl 的影响 和反式 ABP，通过检查 ABP 过度表达的能力或 他们的突变多肽可以阻止细胞转化。