IDENTIFICATION OF TARGETS OF BCR ABL IN THE LEUKEMOGENIC

白血病中 BCR ABL 靶点的识别

基本信息

批准号：
6512760
负责人：
Ruibao Ren
金额：
$ 36.96万
依托单位：
BRANDEIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-05-07 至 2006-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6512760
关键词：
Retroviridae carcinogenesis chimeric proteins chromosome translocation chronic myelogenous leukemia colony stimulating factor gene mutation guanine nucleotide binding protein interleukin 3 laboratory mouse neoplasm /cancer genetics oncoproteins protein structure function selectins site directed mutagenesis transcription factor transfection /expression vector

项目摘要

DESCRIPTION: (Adapted from the investigator's abstract) Our long-term goal is to understand the molecular mechanism by which the bcr-abl oncogene acts in the pathogenesis of chronic myelogenous leukemia (CML). During the previous project period, we have successfully established a mouse CML model where Bcr-Abl efficiently induces a myeloproliferative disease resembling the chronic phase of human CML. We have used this murine CML model to define the roles of domains of Bcr-Abl and of specific signaling events in leukemogenesis. The mouse CML model has also provided a way to study the role played in leukemogenesis by extracellular factors produced by Bcr-Abl target cells, and by the altered interaction of these target cells with the in vivo microenvironment. Since Bcr-Abl alone induces only a myeloproliferative disorder, we recently sought to study the blast transformation of CML by testing if Bcr-Abl and the AML1/MDS1/EVI1 (AME) fusion protein cooperate to efficiently induce acute myelogenous leukemia. AME is a product of the human t(3;21)(q26;q22) translocation found as a secondary mutation in some cases of CML during the blast phase, and in therapy-related myelodysplasia and acute myelogenous leukemia. We found that while AME alone induces an acute myelogenous leukemia with a long latency (5 to 13 mounts), coexpression of Bcr-Able and AME induces a myeloproliferative disorder with accumulation of a large number of immature myeloid cells, resembling the accelerated or myeloid blast phase of CML, with a latency of 1 to 3 months. Building on our progress in several areas and our expertise with in vivo models of leukemia, this proposal aims to understand in greater depth and detail the roles of domains of Bcr-Abl of intracellular signaling events and of extracellular factors affected by Bcr-Abl in the pathogenesis of CML. In addition, this project will begin a detailed examination of the specific role of secondary mutations in the blast transformation of CML. Our specific aims for the project are as follows: 1) To test hypotheses regarding the roles of domains of Bcr-Abl and signaling pathways in Bcr-Abl leukemogenesis. 2) To test the hypotheses that altered expression of cytokine and adhesion molecules plays a role in Bcr-Abl leukemogenesis. 3) To test hypotheses regarding the role of secondary mutations in the molecular mechanism of blastic transformation of CML. These studies will help to further design rational therapeutic interventions for CML and to understand the mechanisms involved in leukemogenesis in general.

描述：（改编自研究者的摘要）我们的长期目标是了解 bcr-abl 癌基因在细胞中发挥作用的分子机制慢性粒细胞白血病（CML）的发病机制。在上一个项目期间期间，我们成功建立了小鼠CML模型，其中Bcr-Abl 有效诱导类似于慢性期的骨髓增生性疾病人类慢性粒细胞白血病。我们使用这个小鼠 CML 模型来定义域的角色 Bcr-Abl 和白血病发生中的特定信号事件。小鼠慢性粒细胞白血病该模型还提供了一种研究在白血病发生中所起的作用的方法 Bcr-Abl 靶细胞产生的细胞外因子，以及改变的这些靶细胞与体内微环境的相互作用。自从 Bcr-Abl 单独仅诱导骨髓增殖性疾病，我们最近试图通过测试 Bcr-Abl 和 AML1/MDS1/EVI1（AME）融合蛋白协同有效诱导急性骨髓性白血病。 AME 是人类 t(3;21)(q26;q22) 的产物在某些 CML 病例中发现易位是继发突变急变期，以及治疗相关的骨髓增生异常和急性骨髓性白血病。我们发现，虽然 AME 单独诱发急性髓性白血病 Bcr-Able 和 AME 的共表达具有较长的潜伏期（5 至 13 个装载），可诱导一种骨髓增生性疾病，伴有大量未成熟细胞的积累髓样细胞，类似于 CML 的加速期或髓样急变期，具有潜伏期1至3个月。立足于我们在多个领域取得的进展以及我们的白血病体内模型的专业知识，该提案旨在了解更深入和详细地了解细胞内 Bcr-Abl 结构域的作用受 Bcr-Abl 影响的信号事件和细胞外因子 CML 的发病机制。此外，该项目将开始详细检查二次突变在急变中的具体作用 CML 的转化。我们该项目的具体目标如下： 1）关于 Bcr-Abl 结构域和信号传导的作用的测试假设 Bcr-Abl 白血病发生的途径。 2）检验改变的假设细胞因子和粘附分子的表达在 Bcr-Abl 中发挥作用白血病发生。 3）检验有关二次突变作用的假设 CML急变转化的分子机制。这些研究将有助于进一步设计合理的 CML 治疗干预措施了解白血病发生的一般机制。