Actin dynamics as a therapeutic target for Bcr-Abl-positive acute lymphoblastic leukemia.

肌动蛋白动力学作为 Bcr-Abl 阳性急性淋巴细胞白血病的治疗靶点。

基本信息

批准号：
8810797
负责人：
ZONGHAN DAI
金额：
$ 45.3万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-22 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8810797
关键词：
Abnormal Cell Actins Acute Lymphocytic Leukemia Animal Model Animals Architecture Aspartic Acid Attenuated Binding Biochemical CDC2 Protein Kinase Cell Adhesion Cell Cycle Cell Cycle Progression Cell Proliferation Cell division Cell model Cell physiology Cells Cellular biology Complex Cytoskeleton Development Disseminated Malignant Neoplasm Event Gene Silencing Genetic Goals Growth Homing Human Imatinib In Vitro Leukemic Cell Malignant Neoplasms Mediating Membrane Mitosis Mitotic Molecular Mus Mutation NIMA Names Neoplasm Metastasis Normal Cell Oncogenic Outcome Study Pathway interactions Pharmacotherapy Phospholipids Phosphorylation Play Process Protein Dephosphorylation Protein Tyrosine Kinase Proteins Recruitment Activity Regulation Regulatory Pathway Research Resistance Role Serine Signal Transduction Structure Testing Therapeutic Tyrosine Tyrosine Kinase Inhibitor Tyrosine Phosphorylation base cancer cell cancer therapy cell growth cell motility design driving force insight leukemia leukemogenesis migration new therapeutic target novel novel diagnostics novel strategies outcome forecast prognostic public health relevance spectrin SH3 domain binding protein 1 therapeutic target trafficking treatment strategy tumor progression

项目摘要

DESCRIPTION (provided by applicant): Deregulation of actin cytoskeleton remodeling is a key event contributes to abnormal growth and migration of leukemic cells. Although numerous regulatory molecules for actin cytoskeleton remodeling have been identified, understanding how these molecules orchestrates to regulate dynamic actin cytoskeleton remodeling in leukemic cells still remains a major challenge. The long-term goal of this proposal is to understand how deregulation of actin cytoskeleton remodeling contributes to leukemia development. The proposed research focuses on a central regulator of actin remodeling, WAVE regulatory complex (WRC). A positive regulation of the WRC signaling by active Abl tyrosine kinases has been well documented. It is not clear, however, how this pathway is deactivated following its activation to achieve actin dynamics and to coordinate with cell cycle progression. We hypothesize that the cyclin dependent kinase 1 (CDK1)-mediated phosphorylation followed by recruitment of the protein interacting with NIMA-1 (Pin1) promotes the tyrosine dephosphorylation and inactivation of WRC at the onset of mitosis. This allows coordination of actin assembly with cell cycle progression. We propose that this deactivation mechanism, together with the activation mechanism mediated by oncogenic Bcr- Abl, plays an important role in regulating Bcr-Abl-positve leukemic cell proliferation and invasion. Therefore, targeting this pathway may have therapeutic potential for imatinib-resistant Bcr-Abl- positive leukemia. In specific aim 1, we will define the role of Pin1 in the regulation of actin dynamics in Bcr-Abl-positive leukemic cells. A Bcr-Abl-positive murine pro-B leukemic cell model, in which WRC is constitutively activated, will be used to determine how CDK1/Pin1 deactivates WRC-mediated actin assembly. Specific aim 2 will test the potential of targeting CKD1 and Pin1 as a therapeutic strategy for treatment of Bcr-Abl-positive leukemia. A combination of pharmacological and genetic approaches is proposed to determine the effect of the inhibition of CDK1 and Pin1 on Bcr-Abl-positive leukemic cell growth, migration, and invasion both in vitro and in animal models. These studies will provide insight into the mechanism by which actin dynamics is regulated in leukemic cells and define the role of the CDK1/Pin1 pathway in Bcr-Abl-induced leukemogenesis. The research is expected to provide new diagnostic and therapeutic targets for treatment of human leukemia in addition to fundamentally advancing the fields of cell biology.

描述（由申请人提供）：肌动蛋白细胞骨架重塑的失调是导致白血病细胞异常生长和迁移的关键事件。尽管已经鉴定出许多肌动蛋白细胞骨架重塑的调节分子，但了解这些分子如何协调调节白血病细胞中的动态肌动蛋白细胞骨架重塑仍然是一个重大挑战。该提案的长期目标是了解肌动蛋白细胞骨架重塑的失调如何促进白血病的发展。拟议的研究重点是肌动蛋白重塑的中央调节器，即 WAVE 调节复合物（WRC）。活性 Abl 酪氨酸激酶对 WRC 信号传导的正向调节已得到充分证明。然而，尚不清楚该途径在激活后如何失活以实现肌动蛋白动力学并与细胞周期进程相协调。我们假设细胞周期蛋白依赖性激酶 1 (CDK1) 介导的磷酸化，随后招募与 NIMA-1 (Pin1) 相互作用的蛋白质，促进有丝分裂开始时的酪氨酸去磷酸化和 WRC 失活。这使得肌动蛋白组装与细胞周期进展相协调。我们认为这种失活机制与致癌 Bcr-Abl 介导的激活机制一起在调节 Bcr-Abl 阳性白血病细胞增殖和侵袭中发挥着重要作用。因此，针对该途径可能对伊马替尼耐药的 Bcr-Abl 阳性白血病具有治疗潜力。在具体目标 1 中，我们将定义 Pin1 在 Bcr-Abl 阳性白血病细胞中肌动蛋白动态调节中的作用。 Bcr-Abl 阳性小鼠 pro-B 白血病细胞模型（其中 WRC 被组成型激活）将用于确定 CDK1/Pin1 如何使 WRC 介导的肌动蛋白组装失活。具体目标 2 将测试靶向 CKD1 和 Pin1 作为治疗 Bcr-Abl 阳性白血病的治疗策略的潜力。提出结合药理学和遗传学方法来确定 CDK1 和 Pin1 的抑制对体外和动物模型中 Bcr-Abl 阳性白血病细胞生长、迁移和侵袭的影响。这些研究将深入了解白血病细胞中肌动蛋白动力学的调节机制，并确定 CDK1/Pin1 通路在 Bcr-Abl 诱导的白血病发生中的作用。除了从根本上推进细胞生物学领域的发展之外，该研究预计还将为人类白血病的治疗提供新的诊断和治疗靶点。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Abl/Abi signaling links WAVE regulatory complex to Cbl E3 ubiquitin ligase and is essential for breast cancer cell metastasis.

Abl/Abi 信号将 WAVE 调节复合物与 Cbl E3 泛素连接酶连接起来，对于乳腺癌细胞转移至关重要。

DOI：
发表时间：
2022-10
期刊：
影响因子：
0
作者：
Jiang, Peixin;Tang, Suni;Hudgins, Hogan;Smalligan, Tate;Zhou, Xue;Kamat, Anuja;Dharmarpandi, Janaki;Naguib, Tarek;Liu, Xinli;Dai, Zonghan
通讯作者：
Dai, Zonghan

CRISPR/CAS9-mediated knockout of Abi1 inhibits p185Bcr-Abl-induced leukemogenesis and signal transduction to ERK and PI3K/Akt pathways.

CRISPR/CAS9 介导的 Abi1 敲除可抑制 p185Bcr-Abl 诱导的白血病发生以及 ERK 和 PI3K/Akt 通路的信号转导。