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Novel NEK2 signaling pathways in myeloma progression - Bauer Diversity Supplement

骨髓瘤进展中的新 NEK2 信号通路 - Bauer Diversity Supplement

基本信息

批准号：
10598777
负责人：
FENGHUANG ZHAN
金额：
$ 16.15万
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/10598777
关键词：
Affect Alternative Splicing Apoptosis Biochemical Biological Markers Cancer Biology Cell Cycle Progression Cell Survival Cells Cessation of life Chromosomal Instability Chromosome abnormality Clinical Complex DNA DNA Sequence DNA Sequence Rearrangement DNA sequencing Data Deubiquitination Development Diagnosis Disease Disease Progression Disease remission Drug resistance EZH2 gene Epigenetic Process Event Future Gene Expression Gene Fusion Generations Genes Genetic Genetic Variation Genome Genomics Hematologic Neoplasms Heparin Lyase Histones Immunotherapy In complete remission Knockout Mice Length Malignant Neoplasms Mediating Messenger RNA Methylation Methyltransferase Modification Multi-Drug Resistance Multiomic Data Multiple Myeloma Mus NIMA Nucleic Acids Numerical Chromosomal Abnormality Oncogenic Outcome Pathway Analysis Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacology Phosphotransferases Plasma Cells Play Polycomb Prevention approach Prognosis Protein-Serine-Threonine Kinases Proteins RNA RNA Splicing Recurrence Relapse Research Residual Neoplasm Resistance Role Sampling Severities Signal Pathway Signal Transduction Solid Neoplasm Survival Rate Technology Testing Third Generation Sequencing Transcript Transgenic Mice Transplantation United States Variant Work base bone chemotherapy epigenomics heparanase high risk histone methyltransferase immune checkpoint blockade improved in vivo insertion/deletion mutation insight mouse model multiple omics nanopore new therapeutic target next generation sequencing novel novel therapeutics prevent programmed cell death ligand 1 proteogenomics relapse patients response single molecule transcriptomics 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- κB/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 a 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.

项目总结