Novel functions of CDK6 in T-cell leukemia progression

CDK6 在 T 细胞白血病进展中的新功能

基本信息

批准号：
10297128
负责人：
Haizhen Wang
金额：
$ 34.44万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10297128
关键词：
Acute T Cell Leukemia Antibodies Apoptosis Binding Blood Platelets CXCR4 Receptors Cell Line Cell Nucleus Cell Proliferation Cells Clinical Correlative Study Cyclin D1 Disease Progression Enzymes Genetic Transcription Glycolysis Goals Human Immune Evasion Immunohistochemistry In Vitro Infiltration Isoenzymes Laboratories Lead Leukemic Cell Malignant Neoplasms Measures Mediating Modeling Molecular Morbidity - disease rate Mus Muscle Mutate Nuclear Nuclear Translocation Organ Patients Phosphorylation Phosphotransferases Play Prognosis Prognostic Marker Promoter Regions Protein Isoforms Proteins Pyruvate Kinase Reactive Oxygen Species Role Site Stains Survival Rate T-Cell Leukemia T-Cell Lymphoma T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Therapeutic Effect Treatment Efficacy Treatment Failure Work anti-PD-L1 base c-myc Genes cancer cell cancer invasiveness chemokine receptor cohort cyclin D3 cyclin-dependent kinase 6 in vivo inhibitor/antagonist knock-down leukemia leukemia/lymphoma mortality mouse model mutant neoplastic cell new therapeutic target novel novel therapeutic intervention overexpression pre-clinical preclinical study prevent prognostic prognostic assays prognostic value programmed cell death ligand 1 relapse patients therapeutically effective translational study treatment strategy

项目摘要

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.

T细胞白血病中治疗失败的最常见原因之一是恶性细胞的传播。这该提案的总体目标是测试抑制CDK6激酶是否有望有效治疗T细胞白血病传播的治疗策略。 Cyclin D3/CDK6是T细胞急性淋巴细胞白血病（T-ALL）和激酶中细胞周期蛋白D/CDK的主要类型 CDK6在T-ALL中的活性显着增强，因为其抑制剂蛋白在超过50％的T-ALL中被突变案例。针对T-ALL治疗的CDK6是有希望的，因为它可以防止白血病细胞增殖并诱导T- 所有凋亡。目前尚不清楚CDK6是否或如何调节T-ALL传播。在这项研究中，我们将阐明了T细胞白血病传播中细胞周期蛋白D3/CDK6的新调节机制。我们获得了大量的初步证据，表明CDK6在T-All传播中起着重要作用调节PFKP的核易位和磷酸化。我们还发现CDK6依赖性核 PFKP的富集可能对T细胞淋巴瘤/白血病具有预后影响。在拟议的工作中，我们将扩展这些发现。在AIM 1中，我们将研究Cyclin D3/CDK6如何调节PFKP核转运至促进白血病入侵。在AIM 2中，我们将确定CDK6介导的PFKP磷酸化如何增加 CXCR4和PD-L1表达以增强白血病细胞传播。在AIM 3中，我们将进行翻译研究核PFKP在T细胞淋巴瘤/白血病中测试核PFKP的预后价值的研究 T细胞淋巴瘤/白血病患者的良好宣布队列，以及对治疗作用的临床前研究 T-ALL小鼠模型上的CDK6特异性降解器。该提议的预期总体影响是阐明CDK6在T-ALL传播中的分子功能，并可能导致新的靶向治疗基于CDK6抑制的策略。