Role of KLHL6 inactivation in mature B-cell malignancies

KLHL6 失活在成熟 B 细胞恶性肿瘤中的作用

基本信息

批准号：
9756339
负责人：
Luca Busino
金额：
$ 42.64万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9756339
关键词：
Affect Animals Apoptosis Apoptotic B cell differentiation B lymphoid malignancy B-Cell Development B-Cell Lymphomas B-Cell Neoplasm B-Lymphocytes BTB/POZ Domain Binding Biological Assay Bone Marrow Bortezomib Cell Line Cell Maturation Cell Proliferation Cell Survival Cell physiology Cells Chronic Chronic Lymphocytic Leukemia Clinical Common Neoplasm Communicable Diseases Data Defect Dependence Disease Disease Progression Dominant-Negative Mutation Enzymes Event Exhibits Female Follicular Lymphoma Functional disorder Genes Goals Hematologic Neoplasms Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Heterogeneity IL6ST gene Immune System Diseases Impairment In Vitro Inhibition of Apoptosis Link Lymphocyte Lymphoid Lymphoid Tissue Lymphomagenesis Maintenance Malignant Neoplasms Mature B-Lymphocyte Measures Medical Genetics Messenger RNA Molecular Multiple Myeloma Mutate Mutation Nature Pathogenesis Pathway interactions Phosphotransferases Proteasome Inhibitor Proteins Proteolysis Proteomics Regulation Research Research Proposals Role Signal Pathway Signal Transduction Structure of aggregated lymphoid follicle of small intestine Structure of germinal center of lymph node System Therapeutic Tonsil Transcript Tumor Suppressor Proteins Ubiquitin base biological adaptation to stress cancer cell cell growth cullin-3 desensitization differentiated B cell experimental study human model in vivo inhibitor/antagonist large cell Diffuse non-Hodgkin&apos s lymphoma loss of function mRNA Decay male mouse model multicatalytic endopeptidase complex mutant novel personalized therapeutic prevent protein degradation response success tumor tumor initiation ubiquitin isopeptidase ubiquitin ligase ubiquitin-protein ligase

项目摘要

Project Summary Mature B-cell neoplasms are the fifth most common neoplasm in both males and females. They arise from B- cells that have entered germinal centers and display great heterogeneity at the clinical and genetic levels. The clinical success of proteasome inhibitors, bortezomib, and E3 ubiquitin ligase inhibitors, lenalinomide for the treatment of multiple myeloma and B-cell lymphomas has made the Ubiquitin pathway a bona fide target for cancer therapeutics. Thus, defining how novel E3 ligases function at a molecular level and investigating their role in B-cell malignancies remains a major research imperative in order to develop more specific therapeutic avenues. KLHL6 is a gene of unknown function that is mutated in mature B-cell malignancies such as chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and multiple myeloma. We have demonstrated that KLHL6 is an E3 ubiquitin ligase and cancer-associated mutations inactivate its catalytic activity. The goals of this research proposal are to define the molecular and cellular functions of KLHL6 with regards substrate degradation and analyze the effects of KLHL6-loss in vivo. Our central hypothesis is that KLHL6 is novel tumor suppressor that may contribute to the pathogenesis of DLBCL and MM by regulating cell proliferation, differentiation and survival.

项目概要成熟 B 细胞肿瘤是男性和女性中第五常见的肿瘤。它们来自B- 已进入生发中心并在临床和遗传水平上表现出巨大异质性的细胞。这蛋白酶体抑制剂硼替佐米和 E3 泛素连接酶抑制剂来那洛胺的临床成功多发性骨髓瘤和 B 细胞淋巴瘤的治疗使泛素途径成为真正的靶点癌症治疗。因此，定义新型 E3 连接酶如何在分子水平上发挥作用并研究它们为了开发更具体的治疗方法，B 细胞恶性肿瘤中的作用仍然是一项重要的研究任务途径。 KLHL6 是一种功能未知的基因，在成熟 B 细胞恶性肿瘤（例如慢性淋巴细胞白血病、弥漫性大 B 细胞淋巴瘤、滤泡性淋巴瘤和多发性骨髓瘤。我们有证明 KLHL6 是一种 E3 泛素连接酶，癌症相关突变使其催化失活活动。本研究计划的目标是定义 KLHL6 的分子和细胞功能关于底物降解并分析体内 KLHL6 丢失的影响。我们的中心假设是 KLHL6是一种新型肿瘤抑制因子，可能通过调节细胞参与DLBCL和MM的发病机制增殖、分化和存活。