IDENTIFICATION OF TARGETS OF BCR ABL IN THE LEUKEMOGENIC

白血病中 BCR ABL 靶点的识别

• 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
• 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

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：（改编自研究者摘要）我们的长期目标是 为了了解bcr-abl癌基因在肿瘤中作用的分子机制， 慢性粒细胞白血病（CML）的发病机制。在上一个项目中， 在此期间，我们成功地建立了Bcr-Abl 有效诱导类似慢性期的骨髓增生性疾病 人类CML我们已经使用这个小鼠CML模型来定义结构域的作用， Bcr-Abl和白血病发生中的特定信号事件。小鼠CML 该模型还提供了一种方法来研究在白血病发生中所起的作用， 由Bcr-Abl靶细胞产生的细胞外因子，以及由改变的 这些靶细胞与体内微环境的相互作用。以来 单独的Bcr-Abl仅诱导骨髓增生性疾病，我们最近试图 通过检测Bcr-Abl和Bcr-Abl的表达， AML 1/MDS 1/EVI 1（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病例中发现的继发性突变是一种易位， 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单独诱导急性髓性白血病， Bcr-Able和AME的共表达具有较长的潜伏期（5至13次）， 一种骨髓增生性疾病，伴有大量未成熟的 髓样细胞，类似于CML的加速期或髓样原始细胞期， 潜伏期1 - 3个月。在我们在若干领域取得进展的基础上， 专业知识与白血病的体内模型，这一建议的目的是了解在 更深入和详细的Bcr-Abl结构域的作用， Bcr-Abl影响的细胞外因子的变化 CML的发病机制。此外，该项目将开始详细的 检查继发性突变在爆炸中的特殊作用 CML的转化我们的具体目标是：1） 检验关于Bcr-Abl结构域和信号传导作用的假设 Bcr-Abl白血病发生途径。2)为了验证那些改变了 细胞因子和粘附分子的表达在Bcr-Abl 白血病发生3)为了验证关于继发性突变作用的假设， CML急变的分子机制。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。