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

描述（由申请人提供）：肌动蛋白细胞骨架重塑的解除是导致白血病细胞异常生长和迁移的关键事件。虽然已经确定了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肌动蛋白细胞骨架的动态重塑仍然是一个主要挑战。这项建议的长期目标是了解解除肌动蛋白细胞骨架重塑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因子，WAVE调节复合体（WRC）。活性Abl酪氨酸激酶对WRC信号的正向调节已经得到了很好的证明。然而，目前尚不清楚该途径如何在激活后失活以实现肌动蛋白动力学并与细胞周期进程协调。我们假设细胞周期蛋白依赖性激酶1 （CDK1）介导的磷酸化随后与NIMA-1 （Pin1）相互作用的蛋白募集促进了有丝分裂开始时WRC的酪氨酸去磷酸化和失活。这允许肌动蛋白组装与细胞周期进程的协调。我们认为这种失活机制与致癌Bcr-Abl介导的激活机制在调节Bcr-Abl阳性白血病细胞的增殖和侵袭中起重要作用。因此，靶向这一途径可能具有治疗伊马替尼耐药Bcr-Abl阳性白血病的潜力。在特定目标1中，我们将定义Pin1在bcr - abl阳性白血病细胞中调节肌动蛋白动力学中的作用。bcr - abl阳性小鼠前b白血病细胞模型，其中WRC被组成性激活，将用于确定CDK1/Pin1如何使WRC介导的肌动蛋白组装失活。特异性目的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。在体外和动物模型中，提出了药理学和遗传学相结合的方法来确定CDK1和Pin1抑制对bcr - abl阳性白血病细胞生长、迁移和侵袭的影响。这些研究将提供对白血病细胞中肌动蛋白动力学调节机制的深入了解，并确定CDK1/Pin1通路在bcr - abl诱导的白血病发生中的作用。该研究有望为人类白血病的治疗提供新的诊断和治疗靶点，并从根本上推动细胞生物学领域的发展。

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.