Understanding resistance mechanisms to protein arginine methyltransransferase Inhibitors in Lymphoma

了解淋巴瘤对蛋白精氨酸甲基转移酶抑制剂的耐药机制

基本信息

批准号：
10668754
负责人：
Michael Kharas
金额：
$ 71.39万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-13 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668754
关键词：
3&apos Untranslated Regions Acceleration Adult Advanced Malignant Neoplasm Antibodies Arginine Automobile Driving B-Cell Lymphomas B-Lymphocytes BCL-2 Protein BCL2 gene Binding Binding Proteins Biology CRISPR screen Cell Line Cell physiology Cells Clinic Clinical Communication Data Dependence Disease Enzymes Epigenetic Process Failure Family Genes Genetic Growth Hematologic Neoplasms Histones Human Impairment Laboratories Lymphoma Lymphoma cell Lymphomagenesis Lysine MYC Family Protein Malignant Neoplasms Mediating Mediator Messenger RNA Methylation Modality Modification Mus Mutation Nature Non-Hodgkin&apos s Lymphoma Oncogenic Oncoproteins Outcome Pathogenesis Patients Play Post-Translational Protein Processing Proliferating Protein Family Protein-Arginine N-Methyltransferase Proteins Publishing RNA Recognition Motif RNA-Binding Proteins Recurrence Resistance Role Sampling Site Solid Neoplasm System Therapeutic Translations Up-Regulation cell growth genome-wide improved in vivo inhibitor inhibitor therapy large cell Diffuse non-Hodgkin&apos s lymphoma leukemia loss of function molecular targeted therapies mouse model mutant new therapeutic target non-histone protein novel novel therapeutic intervention overexpression programs protein expression relapse patients resistance mechanism response small hairpin RNA stem stem cells targeted treatment technological innovation transcriptome translatome tumor tumor eradication

项目摘要

PROJECT SUMMARY/ABSTRACT Non-Hodgkin’s lymphoma (NHL) is among the most common cancers and despite current therapies many patients relapse from their disease. Recent discoveries have implicated epigenetic mechanisms and non- classical oncogenic programs as dysregulated in patients with B-cell lymphoma. Protein arginine methyltransferase-5 (PRMT5), the major enzyme responsible for the arginine symmetric dimethylation of histones and non-histone proteins, plays an important role in lymphomagenesis, controlling the growth of transformed B cells. PRMT5 is overexpressed in lymphoma and may represent a novel therapeutic target for this disease. In order to assess what regulators drive resistance, we performed a genome wide CRISPR screen. Surprisingly, we uncovered the RNA binding protein MUSASHI2 (MSI2) as the top hit. MSI2 is an RNA binding protein that has been implicated as a stem related protein that is the most highly expressed in the most aggressive cancers but its role in B-cell lymphoma is not known. Our preliminary data suggests that MSI2 is highly expressed in lymphomas and reduction reduces proliferation which is further reduced by PRMT5 inhibition. We also discovered new post-translational modifications mediated by PRMT1 and PRMT5 in B-cell lymphoma and demonstrated a functional requirement for these newly discovered modifications. We propose to study this new PRMT-MSI2 axis in driving lymphomagenesis using genetic mouse models, human lymphoma cell lines and patient samples. Furthermore, we utilize technological innovations to study direct MSI2 targets and the mechanism for how MSI2 mediates resistance to PRMT5 inhibition in lymphoma. These studies have broad implication to how RBPs can become dysregulated and their function controlled by PRMTs in B-cell lymphoma.

项目摘要/摘要非霍奇金的淋巴瘤（NHL）是最常见的癌症和目的地疗法之一患者从自己的疾病中传递。最近的发现实施了表观遗传机制和非 - B细胞淋巴瘤患者的经典致癌程序失调。蛋白精氨酸甲基转移酶5（PRMT5），这是负责精氨酸对称二甲基化的主要酶希斯孔和非固定蛋白在淋巴作用中起着重要作用，控制着生长转化的B细胞。 PRMT5在淋巴瘤中过表达，可能代表一个新颖的治疗靶点这种疾病。为了评估哪种调节器驱动阻力，我们进行了基因组广泛的CRISPR屏幕。令人惊讶的是，我们发现了RNA结合蛋白Musashi2（MSI2）的最高命中率。 MSI2是RNA结合蛋白质与茎相关的蛋白质含量最高。侵略性癌症，但其在B细胞淋巴瘤中的作用尚不清楚。我们的初步数据表明MSI2是在淋巴瘤中高度表达和还原可减少增殖，这进一步降低了PRMT5抑制作用。我们还发现了B细胞淋巴瘤中PRMT1和PRMT5介导的新的翻译后修饰并证明了这些新发现的修改的功能要求。我们建议研究这一点新的PRMT-MSI2轴在使用遗传小鼠模型，人淋巴瘤细胞系驱动淋巴瘤发生中和患者样品。此外，我们利用技术创新来研究直接MSI2目标和 MSI2如何介导对淋巴瘤中PRMT5抑制的抗性的机制。这些研究广泛对RBP的失调以及其功能由B细胞淋巴瘤中的PRMT控制的影响。