Functional study of cyclin D3/CDK6 in regulating T-ALL progression via tumor cellular ROS and T cell

细胞周期蛋白D3/CDK6通过肿瘤细胞ROS和T细胞调节T-ALL进展的功能研究

• 批准号: 10244667
• 负责人: Haizhen Wang
• 金额: $ 17.16万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-01-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10244667
• 关键词: Ablation; Acute Lymphocytic Leukemia; Acute T Cell Leukemia; Address; Apoptosis; Automobile Driving; CD8B1 gene; Cell Cycle; Cell Proliferation; Cells; Centers of Research Excellence; Cytotoxic T-Lymphocytes; Enzymes; Equilibrium; Glycolysis; Methods; Oxidants; Oxidation-Reduction; Play; Population; Regulatory T-Lymphocyte; Role; Signal Transduction; South Carolina; Stress; T-Lymphocyte; cyclin D3; cyclin-dependent kinase 6; tumor; tumor microenvironment; tumor progression

Cyclin D3 and cyclin-dependent kinases 6(CDK6) are components of the core cell cycle machinery driving cell proliferation, and generally amplified in T acute lymphoblastic leukemia (T-ALL). The pro-survival function of cyclin D3/CDK6 in T-ALL cells via phosphorylating/inactivating PFKP and PKM2 (two key enzymes in glycolysis) is recently addressed. Targeting cyclin D3/CDK6 is a promising method for T-ALL therapy. As tumor microenvironment cell play critical roles in regulating tumor progression, it is critical/urgent to understand the functions of cyclin D3/CDK6 in tumor microenvironment cells. Our preliminary study showed that cyclin D3/CDK6 expression was significantly upregulated in T cells under activation condition. Ablation of cyclin D3 or CFK6 dramatically decreased regulatory T cell (Tregs) population without inducing cell apoptosis. Tregs promote tumor progression by inhibiting T help cells and CD8+ cytotoxic T cells. We therefore hypothesized that cyclin D3/CDK6 regulate T-ALL progression via T-ALL prosurvival and Tregs differentiation. This study will provide the rational to treat T-ALL by targeting cyclin D3/CDK6.

细胞周期蛋白 D3 和细胞周期蛋白依赖性激酶 6 (CDK6) 是驱动细胞增殖的核心细胞周期机制的组成部分，通常在 T 急性淋巴细胞白血病 (T-ALL) 中扩增。最近，T-ALL 细胞中细胞周期蛋白 D3/CDK6 通过磷酸化/灭活 PFKP 和 PKM2（糖酵解中的两种关键酶）发挥的促生存功能得到了解决。靶向细胞周期蛋白 D3/CDK6 是 T-ALL 治疗的一种有前景的方法。由于肿瘤微环境细胞在调节肿瘤进展中发挥着关键作用，因此了解细胞周期蛋白 D3/CDK6 在肿瘤微环境细胞中的功能至关重要/紧迫。我们的初步研究表明，激活条件下T细胞中cyclin D3/CDK6的表达显着上调。细胞周期蛋白 D3 或 CFK6 的消除可显着减少调节性 T 细胞 (Treg) 数量，但不会诱导细胞凋亡。 Tregs 通过抑制 T 辅助细胞和 CD8+ 细胞毒性 T 细胞来促进肿瘤进展。因此，我们假设细胞周期蛋白 D3/CDK6 通过 T-ALL 促存活和 Tregs 分化来调节 T-ALL 进展。这项研究将为通过靶向细胞周期蛋白 D3/CDK6 治疗 T-ALL 提供理论依据。