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：
9883275
负责人：
FENGHUANG ZHAN
金额：
$ 34.75万
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/9883275
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 Expression Profiling FDA approved Gene Expression Genes Genetic Goals Hematologic Neoplasms Human Immuno-Chemotherapy Immunocompetent Immunomodulators Immunotherapy In Vitro In complete remission Knockout Mice Light 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 Pharmacology Plasma Cells Prevention approach Proteasome Inhibitor Protein-Serine-Threonine Kinases Proteins Relapse Reporting Research Residual Neoplasm Resistance Role Sampling Signal Pathway Signal Transduction Solid Neoplasm Structure 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 improved in vivo inhibitor/antagonist innovation insight mouse model neoplastic cell novel novel therapeutic intervention novel therapeutics outcome forecast prevent programmed cell death ligand 1 relapse risk response tumor growth

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）是浆细胞恶性肿瘤，其特征是广泛的结构和数值染色体异常。通过比较样品的连续基因表达谱（GEP）基线，在强化化疗和继电器期间，我们已经确定了染色体不稳定性（CIN）与MM疾病中预后不良有关的基因。 CIN基因之一，串行硫代激酶 NEK2，是完全缓解（CR）患者骨髓瘤细胞中最显着上调的基因（CR）串联移植后化学疗法期间早期的早期残留疾病（MRD）和退休时。我们已经表明，NEK2的药理学或遗传抑制会延迟肿瘤的生长并诱导细胞骨髓瘤的凋亡和NEK2的高表达也与许多其他结果有关癌症。去泛素酶（DUB）USP7稳定NEK2蛋白，导致NF-激活 B/肝素酶途径，也参与骨骼破坏。但是，尚不清楚nek2是否也激活USP7。此外，我们发现NEK2负调节PD-L1表达，很可能是通过表观遗传修饰。高风险的骨髓瘤细胞显示较低的PD-L1表达，对免疫检查点封锁。因此，我们假设NEK2促进了骨髓瘤细胞存活，药物通过激活去泛素酶USP7和组蛋白甲基转移酶来抗性和疾病进展 EZH2。为了严格检验这一假设，我们将：（1）确定主要的去泛素化目标由NEK2-转基因小鼠由Nek2表达不同的NEK2-转基因小鼠调节控件。我们将专注于选择可能的蛋白质作为原理证明，以确立USP7的作用该复合物中的信号集线器。（2）确定NEK2抑制免疫反应的机制使用NEK2敲除小鼠和生化方法在骨髓瘤细胞中进行检查点阻断。和（3）开发新型免疫疗法，用于使用原发性骨髓瘤细胞，A 遗传NEK2敲除小鼠模型和骨髓瘤小鼠模型。由强大的初步数据支持为此应用提供强大的理由，拟议的研究被毒化以促进新颖的针对性预防和治疗骨髓瘤进展和缓解的方法。我们预测我们的结果将延伸到骨髓瘤之外，还适用于其他血液学和实体瘤。