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

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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.