AbI-Abi signaling in neoplastic hematopoiesis

描述（由申请人提供）：本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了两种Abl相互作用物（Abl）蛋白，Abi-1和Abi-2，其结合细胞Abl（c-Abl）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信号通路的关键调节因子，Rac信号通路在造血细胞迁移和归巢的调控中起重要作用。另一方面，Abi-2在表达Bcr-Abl的造血细胞中被降解。Abi-2的表达在从侵袭性Bcr-Abl阳性白血病患者分离的细胞系和骨髓细胞中丢失。这一假设是基于Bcr-Abl向Abi-1和Abi-2的信号转导可能在Bcr-Abl诱导的白细胞生成中起重要作用的假设。我们推测Abi-1的酪氨酸磷酸化和随后的Rac通路的激活可能是Bcr-Abl诱导白血病细胞骨架功能和转移表型异常的重要机制。我们认为，Abi-2的丢失可能是Bcr-Abl阳性白血病进展的一个组成部分。因此，本提案的目的是研究突变Bcr-Abl的白血病发生潜力，该突变Bcr-Abl在Abi-1和Abi-2信号传导中存在缺陷;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，设计了生物化学和遗传学方法来破坏或阻断Abi-1和Abi-2在造血系统中的信号转导。将采用骨髓移植小鼠模型来评估Abi信号传导的破坏对Bcr-Abl诱导的白血病发生的影响。将确定对信号转导调节至关重要的Abi-1和Abi-2序列，并进行突变以进行功能分析。总的来说，这些研究可以提供深入了解细胞迁移，归巢和转移的调节机制。了解阿比特龙信号在肿瘤性造血中的作用，将有助于开发更有效的治疗人类白血病的疗法。

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.