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。细胞周期蛋白D3/CDK6通过磷酸化/失活PFKP和PKM2（糖酵解的两个关键酶）在T-ALL细胞中的促生存功能最近得到了解决。靶向细胞周期蛋白D3/CDK6是一种很有前途的T-ALL治疗方法。肿瘤微环境细胞在调节肿瘤进展中起着至关重要的作用，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/迫切。我们的初步研究表明，在活化条件下，T细胞cyclin D3/CDK6的表达显著上调。cyclin D3或CFK6的消融可显著降低调节性T细胞（Tregs）数量，而不诱导细胞凋亡。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促生存和Tregs分化调节T-ALL进展。本研究将为靶向细胞周期蛋白D3/CDK6治疗T-ALL提供依据。

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.