Novel functions of CDK6 in T-cell leukemia progression

T细胞白血病治疗失败的最常见原因之一是恶性细胞的扩散。这个 这项提案的首要目标是测试抑制CDK6激酶是否具有有效的前景 播散性T细胞白血病的治疗策略。 细胞周期蛋白D3/CDK6是T细胞急性淋巴细胞白血病(T-ALL)中细胞周期蛋白D/CDK的主要类型，而细胞周期蛋白D3/CDK6是T细胞急性淋巴细胞白血病(T-ALL)中最常见的细胞周期蛋白 T-ALL中CDK6的活性显著增强，其抑制蛋白在50%以上的T-ALL中发生突变 案子。靶向CDK6用于T-ALL治疗是有希望的，因为它可以防止白血病细胞的增殖并诱导T-ALL 所有的细胞凋亡。目前尚不清楚CDK6是否或如何调控T-ALL的传播。在这项研究中，我们将 阐明细胞周期蛋白D3/CDK6在T细胞白血病扩散中的新调控机制。我们 获得大量的初步证据表明CDK6在T-ALL的传播中发挥重要作用 调节PFKP的核转位和磷酸化。我们还发现依赖CDK6的核 PFKP的升高可能对T细胞淋巴瘤/白血病的预后有影响。在拟议的工作中，我们将 扩展这些发现。在目标1中，我们将研究细胞周期蛋白D3/CDK6如何调节PFKP核转位 促进白血病侵袭。在目标2中，我们将确定CDK6介导的PFKP磷酸化如何增加 CXCR4和PD-L1的表达促进白血病细胞扩散。在目标3中，我们将执行一项翻译 扩大临床试验检测核PFKP对T细胞淋巴瘤/白血病预后价值的研究 对T细胞淋巴瘤/白血病患者进行了详细的队列研究，并进行了一项临床前研究 T-ALL小鼠模型上的CDK6特异性降解剂。这项提议的预期总体影响是，它可能 阐明CDK6在T-ALL扩散中的分子功能，可能导致新的靶向治疗 基于CDK6抑制的策略。

One of the most common causes of treatment failure in T-cell leukemia is dissemination of malignant cells. The overarching goal of this proposal is to test whether inhibition of CDK6 kinase holds promise as an effective therapeutic strategy for treatment of T-cell leukemia dissemination. Cyclin D3/CDK6 is the major type of cyclin D/CDK in T-cell acute lymphoblastic leukemia (T-ALL), and kinase activity of CDK6 in T-ALL is dramatically enhanced as its inhibitor proteins are mutated in over 50% of T-ALL cases. Targeting CDK6 for T-ALL therapy is promising as it prevents leukemia cell proliferation and induces T- ALL apoptosis. It is not clear whether or how CDK6 regulates T-ALL dissemination. In this study, we will elucidate the novel regulatory mechanism of cyclin D3/CDK6 in T-cell leukemia dissemination. We obtained substantial preliminary evidence to show that CDK6 plays an important role in T-ALL dissemination by regulating nuclear translocation and phosphorylation of PFKP. We also found that CDK6-dependent nuclear enrichment of PFKP may have a prognostic impact in T-cell lymphoma/leukemia. In the proposed work, we will extend these findings. In Aim 1, we will examine how cyclin D3/CDK6 regulates PFKP nuclear translocation to promote leukemia invasion. In Aim 2, we will determine how CDK6 mediated PFKP phosphorylation increases CXCR4 and PD-L1 expression to enhance leukemia cell dissemination. In Aim 3, we will perform a translational study to test the prognostic value of nuclear PFKP in T-cell lymphoma/leukemia using an expanded clinically well-annotated cohort of T cell lymphoma/leukemia patients, and a pre-clinical study of the therapeutic effect of a CDK6 specific degrader on T-ALL mouse models. The expected overall impact of this proposal is that it may elucidate the molecular function of CDK6 in T-ALL dissemination, and it may lead to novel targeted therapeutic strategies based on CDK6 inhibition.