AbI-Abi signaling in neoplastic hematopoiesis

肿瘤造血中的 AbI-Abi 信号传导

• 批准号: 7027765
• 负责人: ZONGHAN DAI
• 金额: $ 6.28万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7027765
• 关键词: B cell receptor; SDS polyacrylamide gel electrophoresis; biological signal transduction; carcinogenesis; cell migration; cell proliferation; flow cytometry; genetically modified animals; green fluorescent proteins; hematopoiesis; immunoprecipitation; laboratory mouse; leukemia; leukopoiesis; metastasis; neoplastic process; oncoproteins; phosphorylation; polymerase chain reaction; protein binding; protein tyrosine kinase; protooncogene; southern blotting; western blottings; yeast two hybrid system

DESCRIPTION (provided by applicant): The overall objective of this proposal is to delineate the mechanisms associated with Bcr-Abl-induced leukemogenesis. Previous studies have identified two Abl interactor (Abi) proteins, Abi-1 and Abi-2, that bind to cellular Abl (c-Abl) and are substrates of Abl tyrosine kinase. Abi-1 is tyrosine-phosphorylated in hematopoietic cells transformed by Bcr-Abl. Recent studies indicate that Abi-1 is a key regulator of Rac signaling, a pathway important for regulation of hematopoietic cell migration and homing. Abi-2, on the other hand, is degraded in Bcr-Abl-expressing hematopoietic cells. The expression of Abi-2 is lost in cell lines and bone marrow cells isolated from patients with aggressive Bcr-Abl-positive leukemia. This proposal is based on the hypothesis that the signal transduction from Bcr-Abl to Abi-1 and Abi-2 may play an important role in Bcr-Abl-induced leukernogenesis. We postulate that the tyrosine phosphorylation of Abi-1 and subsequent activation of Rac pathway may represent an important mechanism by which Bcr-Abl induces abnormalities of cytoskeletal function and metastatic phenotype in leukemic cells. We believe that loss of Abi-2 may be a component in the progression of Bcr-Abl-positive leukemia. The goals of this proposal, therefore, are to examine the leukemogenic potential of a mutant Bcr-Abl that is defective in signaling to Abi-1 and Abi-2; to determine the role of Abi-1 and Abi-2 in Bcr-Abl-induced leukemogenesis; and to define the mechanisms by which Bcr-Abl regulates Abi signal transduction. To achieve these goals, biochemical and genetic approaches are designed to disrupt or inactivate signal transduction of Abi-1 and Abi-2 in hematopoietic system. Bone marrow transplant mouse models will be employed to evaluate the effect of disruption of Abi signaling on Bcr-Abl-induced leukemogenesis. Sequences in Abi-1 and Abi-2 that are critical for regulation of signal transduction will be defined and mutations wilt be made for functional analysis. Collectively, these studies may provide insight into the regulatory mechanisms of cell migration, homing, and metastasis. Understanding the role of Abi signaling in neoplastic hematopoiesis should shed light on development of more effective therapies for the treatment of human leukemia.

描述（由申请人提供）：该提案的总体目标是描述与 Bcr-Abl 诱导的白血病发生相关的机制。先前的研究已经鉴定出两种 Abl 相互作用蛋白 (Abi)，Abi-1 和 Abi-2，它们与细胞 Abl (c-Abl) 结合，并且是 Abl 酪氨酸激酶的底物。 Abi-1 在 Bcr-Abl 转化的造血细胞中被酪氨酸磷酸化。最近的研究表明，Abi-1 是 Rac 信号传导的关键调节因子，而 Rac 信号传导是调节造血细胞迁移和归巢的重要途径。另一方面，Abi-2 在表达 Bcr-Abl 的造血细胞中被降解。从侵袭性 Bcr-Abl 阳性白血病患者分离的细胞系和骨髓细胞中，Abi-2 的表达缺失。该提议基于以下假设：从 Bcr-Abl 到 Abi-1 和 Abi-2 的信号转导可能在 Bcr-Abl 诱导的白细胞生成中发挥重要作用。我们推测 Abi-1 的酪氨酸磷酸化和随后 Rac 通路的激活可能代表 Bcr-Abl 诱导白血病细胞细胞骨架功能异常和转移表型的重要机制。我们认为 Abi-2 的缺失可能是 Bcr-Abl 阳性白血病进展的一个组成部分。因此，该提案的目标是检查突变型 Bcr-Abl 的致白血病潜力，该突变型 Bcr-Abl 在向 Abi-1 和 Abi-2 发出信号方面存在缺陷；确定 Abi-1 和 Abi-2 在 Bcr-Abl 诱导的白血病发生中的作用；并确定 Bcr-Abl 调节 Abi 信号转导的机制。为了实现这些目标，设计了生化和遗传学方法来破坏或灭活造血系统中 Abi-1 和 Abi-2 的信号转导。骨髓移植小鼠模型将用于评估 Abi 信号传导破坏对 Bcr-Abl 诱导的白血病发生的影响。 Abi-1 和 Abi-2 中对于信号转导调节至关重要的序列将被定义，并且将进行突变以进行功能分析。总的来说，这些研究可以深入了解细胞迁移、归巢和转移的调节机制。了解 Abi 信号在肿瘤性造血中的作用应该有助于开发更有效的人类白血病疗法。