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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细胞白血病治疗失败的最常见原因之一是恶性细胞的扩散。的这项建议的首要目标是测试抑制CDK 6激酶是否有望作为一种有效的治疗方法。用于治疗T细胞白血病播散的治疗策略。细胞周期蛋白D3/CDK 6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，而激酶 CDK 6在T-ALL中的活性显著增强，因为其抑制剂蛋白在超过50%的T-ALL中发生突变例靶向CDK 6用于T-ALL治疗是有希望的，因为它可以防止白血病细胞增殖并诱导T细胞增殖。 ALL凋亡。目前尚不清楚CDK 6是否或如何调节T-ALL传播。在这项研究中，我们将阐明细胞周期蛋白D3/CDK 6在T细胞白血病播散中的新调控机制。我们获得了大量的初步证据，表明CDK 6在T-ALL传播中起重要作用，调节PFKP的核转位和磷酸化。我们还发现，依赖CDK 6的细胞核 PFKP的富集可能对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。在目的1中，我们将研究细胞周期蛋白D3/CDK 6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CDK 6介导的PFKP磷酸化如何增加 CXCR 4和PD-L1表达增强白血病细胞播散。在目标3中，我们将执行一个一项使用扩大的临床试验检测T细胞淋巴瘤/白血病细胞核PFKP的预后价值的研究一个注释良好的T细胞淋巴瘤/白血病患者队列，以及一项关于在T-ALL小鼠模型上的CDK 6特异性降解剂。这一提议的预期总体影响是，阐明CDK 6在T-ALL播散中的分子功能，并可能导致新的靶向治疗基于CDK 6抑制的策略。