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Novel NEK2 signaling pathways in myeloma progression

骨髓瘤进展中的新 NEK2 信号通路

基本信息

批准号：
10626137
负责人：
FENGHUANG ZHAN
金额：
$ 34.07万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626137
关键词：
Ablation Apoptosis Autologous Stem Cell Transplantation Behavior Biochemical Biological Assay Biology Cell Survival Cells Chromosomal Instability Clinical Complex Data Deubiquitination Development Disease Disease Progression Disease remission Drug resistance EZH2 gene Epigenetic Process FDA approved Gene Expression Genes Genetic Goals HIF1A gene Hematologic Neoplasms Human Immunocompetent Immunotherapy In Vitro In complete remission Knockout Mice Link Malignant Neoplasms Mediating Methylation Modification Multiple Myeloma Mus NFKB Signaling Pathway Network-based Newly Diagnosed Numerical Chromosomal Abnormality Oncoproteins Outcome PD-1/PD-L1 PDL1 inhibitors PTEN gene Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Plasma Cells Prevention approach Probability Prognosis Proteasome Inhibitor Protein-Serine-Threonine Kinases Proteins Relapse Reporting Research Residual Neoplasm Resistance Role Sampling Signal Pathway Signal Transduction Solid Neoplasm Structural Chromosomal Abnormality TP53 gene TRAF6 gene Testing Transgenic Mice Transplantation Tumor Suppressor Proteins Ubiquitination anti-PD-1/PD-L1 anti-PD-L1 therapy bone cell growth chemotherapy cytotoxicity heparanase high risk histone methyltransferase immune checkpoint blockade immune modulating agents improved in vivo inhibitor innovation insight mouse model neoplastic cell novel novel therapeutic intervention novel therapeutics pharmacologic prevent programmed cell death ligand 1 response tumor growth ubiquitin isopeptidase

项目摘要

Project Summary Multiple Myeloma (MM) is a plasma cell malignancy characterized by extensive structural and numerical chromosomal abnormalities. By comparing consecutive gene expression profiles (GEP) of samples at baseline, during intensive chemotherapy and at relapse, we have identified chromosomal instability (CIN) genes associated with poor prognosis in MM disease. One of the CIN genes, the serine-threonine kinase NEK2, is the most significantly upregulated gene in myeloma cells in patients in complete remission (CR) with minimal residual disease (MRD) and at relapse early during chemotherapy following tandem transplantations. We have shown that pharmacological or genetic inhibition of NEK2 delays tumor growth and induces cell apoptosis in myeloma and high expression of NEK2 has also been related to poor outcomes in many other cancers. The deubiquitinase (DUB) USP7 stabilizes NEK2 protein resulting in the activation of the NF- B/heparanase pathway, also involved in bone destruction. However, it is unknown whether NEK2 also activates USP7. In addition, we have found that NEK2 negatively regulates PD-L1 expression, most likely via epigenetic modification. High-risk myeloma cells show low levels of PD-L1 expression and are resistant to immune checkpoint blockade. Therefore, we hypothesize that NEK2 promotes myeloma cell survival, drug resistance, and disease progression by activating the deubiquitinase USP7 and the histone methyltransferase EZH2. In order to rigorously test this hypothesis, we will: (1) Identify the major deubiquitination targets regulated by the Nek2-Usp7 complex using Nek2-transgenic mice with varying levels of Nek2 expression and controls. We will focus on selecting probable proteins as a proof-of-principle to establish the role of Usp7 as the signaling hub in this complex. (2) Determine the mechanisms by which NEK2 inhibits responses to immune checkpoint blockade in myeloma cells using Nek2-knockout mice and biochemical approaches. And, (3) Develop novel immune therapies for drug-resistant and relapsed myelomas using primary myeloma cells, a genetic Nek2-knockout mouse model, and a myeloma mouse model. Supported by strong preliminary data that provide strong rationale for this application, the proposed research is poised to facilitate novel, targeted approaches to the prevention and treatment of myeloma progression and relapse. We predict that our results will extend beyond myeloma and also apply to other hematological and solid tumors.

项目摘要多发性骨髓瘤（MM）是一种浆细胞恶性肿瘤，其特征在于广泛的结构和数量染色体异常通过比较连续的基因表达谱（GEP）的样品，在基线、强化化疗期间和复发时，我们发现了染色体不稳定性（CIN）与MM疾病预后不良相关的基因CIN基因之一，丝氨酸-苏氨酸激酶 NEK 2是完全缓解（CR）患者骨髓瘤细胞中最显著上调的基因，最小残留病（MRD）和双次移植后化疗早期复发。我们已经证明，NEK 2的药理学或遗传学抑制延缓肿瘤生长并诱导细胞凋亡。骨髓瘤中的细胞凋亡和NEK 2的高表达也与许多其他肿瘤的不良结局有关，癌的去泛素化酶（DUB）USP 7稳定NEK 2蛋白，导致NF-κ B活化。 β B/乙酰肝素酶途径，也参与骨破坏。然而，目前尚不清楚NEK 2是否也激活USP 7。此外，我们发现NEK 2负调节PD-L1表达，最有可能是通过表观遗传修饰高风险骨髓瘤细胞显示低水平的PD-L1表达，并且对免疫检查点阻断。因此，我们假设NEK 2促进骨髓瘤细胞存活，药物治疗，通过激活去泛素化酶USP 7和组蛋白甲基转移酶， EZH2.为了严格检验这一假设，我们将：（1）确定主要的去泛素化靶点使用具有不同Nek 2表达水平的Nek 2转基因小鼠，对照我们将重点选择可能的蛋白质作为原理证明，以确定Usp 7的作用，这里的信号中心(2)确定NEK 2抑制免疫应答的机制使用Nek 2敲除小鼠和生物化学方法在骨髓瘤细胞中进行检查点阻断。（3）使用原发性骨髓瘤细胞开发耐药和复发性骨髓瘤的新型免疫疗法， Nek 2基因敲除小鼠模型和骨髓瘤小鼠模型。在强有力的初步数据的支持下，为这一应用提供了强有力的理由，拟议的研究准备促进新的，有针对性的预防和治疗骨髓瘤进展和复发的方法。我们预测我们的结果将扩展到骨髓瘤之外，也适用于其他血液肿瘤和实体瘤。