IDENTIFICATION OF TARGETS OF BCR ABL IN THE LEUKEMOGENIC

描述：(根据调查人员的摘要改编)我们的长期目标是 为了解bcr-abl癌基因在乳腺癌中作用的分子机制。 慢性粒细胞白血病的发病机制。在之前的项目中 期间，我们成功地建立了小鼠CML模型，其中BCR-Abl 有效地诱导类似慢性期的骨髓增生性疾病 人类慢性粒细胞白血病。我们已经使用这个小鼠CML模型来定义结构域的角色 Bcr-Abl和白血病发生中特定信号事件的表达。鼠标慢性粒细胞白血病 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 Bcr-Abl靶细胞产生的细胞外因子及其改变 这些靶细胞与体内微环境的相互作用。自.以来 BCR-Abl单独只能诱导一种骨髓增生性疾病，我们最近试图 检测bcr-abl和bcr-abl对慢性粒细胞白血病BLAST转化的研究 AML1/MDS1/EVI1(AME)融合蛋白协同高效诱导急性白血病 骨髓性白血病。AME是人类t(3；21)(q26；q22)的产物 易位在某些CML病例中被发现为继发性突变 急性期，并在治疗相关的骨髓发育不良和急性髓系细胞增生症 白血病。我们发现，虽然AME单独诱导急性髓系白血病 在潜伏期较长(5-13个)的情况下，bcr-able和AME共表达可诱导 一种伴有大量未成熟细胞积聚的骨髓增生性疾病 髓系细胞，类似于慢性粒细胞白血病的加速或髓系原始细胞阶段，具有 潜伏期为1至3个月。在几个领域取得进展的基础上，我们的 在体内白血病模型方面的专业知识，这项建议旨在了解 更深入和详细地研究细胞内bcr-Abl结构域的作用 Bcr-Abl对心肌细胞内信号转导事件及细胞外因子的影响 慢性粒细胞白血病的发病机制。此外，该项目还将开始一项详细的 继发性突变在BLAST中的特殊作用 慢性粒细胞白血病的转型。我们对该项目的具体目标如下：1) 关于bcr-abl结构域和信号转导作用的测试假设 Bcr-abl白血病发生的途径。2)检验更改后的假设 细胞因子和黏附分子的表达在bcr-abl中的作用 白血病的发生。3)检验关于次级突变作用的假设 在慢性粒细胞白血病急变期的分子机制中。这些研究将 帮助进一步设计CML的合理治疗干预措施，并 从总体上了解白血病发生的机制。

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.