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：
10364396
负责人：
Luca Busino
金额：
$ 40.63万
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 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10364396
关键词：
Accounting Agammaglobulinaemia tyrosine kinase Alleles Animals B lymphoid malignancy B-Cell Antigen Receptor B-Cell Lymphomas B-Lymphocytes BCL6 gene Biological Bortezomib Cancer Etiology Cell Line Cell Proliferation Cells Cessation of life Chemicals Clinical Complex Coupled Cyclophosphamide Data Development Doxorubicin Drug resistance FDA approved Gene Expression Genes Genetic Transcription Glues Goals Growth Hematological Disease Human Impairment Inflammation Investigation Knock-out Knockout Mice Link Lymphoma Lymphoma cell Lymphomagenesis Lymphoproliferative Disorders Malignant Neoplasms Mature B-Lymphocyte Membrane Modeling Molecular Mus Mutate Mutation NOTCH1 gene Neoplasms Non-Hodgkin&apos s Lymphoma Oncogenic Pathogenesis Pathway interactions Patients Penetrance Phenotype Prednisone Proteasome Inhibitor Receptor Inhibition Receptor Signaling Recurrence Refractory Regimen Regulation Relapse Reporting Resistance Role Series Signal Pathway Signal Transduction Therapeutic Treatment Efficacy Tumor Suppressor Genes Tumor Suppressor Proteins Tyrosine Kinase Inhibitor Ubiquitin Up-Regulation Vincristine aged base cancer cell cell transformation gain of function mutation gamma secretase genetic signature in vivo inhibitor large cell Diffuse non-Hodgkin&apos s lymphoma mouse model multicatalytic endopeptidase complex novel patient derived xenograft model personalized therapeutic programs protein degradation rituximab scaffold success tumor tumorigenesis ubiquitin ligase ubiquitin-protein ligase

项目摘要

Project Summary Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma accounting for about 32,000 new cases per year and leading to death in over 40% of cases. This proposal seeks to investigate the biological significance of KLHL6, a gene mutated in mature B-cell cancers, with DLBCL displaying the highest rate of mutations. KLHL6 assembles into a functional CULLIN-RING Ubiquitin ligase (CRL) complex and cancer-associated mutations inhibit KLHL6 interaction to CULLIN3, resulting in loss of activity to transfer ubiquitin chains. In this proposal, we investigate KLHL6 as a master regulator and tumor suppressor of the NOTCH signaling. An investigation of the cell autonomous and drug resistance in murine model of DLBCL as well as patient derived DLBLC xenotransplants will be pursed. Building up on our data, the central hypothesis of this proposal is that deregulation of the KLHL6 function is crucial to lymphomagenesis and impacts therapy. Thus, we aim in modeling loss of Khll6 in a mouse model of DLBCL (Aim1) and we will study how impairment of the NOTCH pathway impacts the therapeutic efficacy of B-cell receptor inhibition in DLBCL (Aim2). Overall, this proposal investigates the mechanisms of DLBCL pathogenesis and treatment. The clinical success of proteasome inhibitors, bortezomib, and E3 ubiquitin ligase glues for the treatment of hematologic diseases 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 inflammation is critical in order to develop more specific therapeutic avenues.

项目概要弥漫性大 B 细胞淋巴瘤 (DLBCL) 是非霍奇金淋巴瘤最常见的亚型每年约有 32,000 个新病例，超过 40% 的病例导致死亡。该提案旨在研究 KLHL6（一种在成熟 B 细胞癌中突变的基因）与 DLBCL 的生物学意义显示出最高的突变率。 KLHL6 组装成功能性 CULLIN-RING 泛素连接酶 (CRL) 复合物和癌症相关突变抑制 KLHL6 与 CULLIN3 的相互作用，导致转移泛素链的活性。在本提案中，我们研究了 KLHL6 作为主调节因子和肿瘤 NOTCH 信号传导的抑制器。小鼠细胞自主性和耐药性的研究 DLBCL 模型以及患者衍生的 DLBLC 异种移植物将被开发。以我们的数据为基础，该提案的中心假设是 KLHL6 功能的失调对于淋巴瘤的发生至关重要和影响治疗。因此，我们的目标是在 DLBCL 小鼠模型中模拟 Khll6 的丢失 (Aim1)，并且我们将研究 NOTCH 通路损伤如何影响 B 细胞受体抑制的治疗效果 DLBCL（目标2）。总体而言，该提案研究了 DLBCL 的发病机制和治疗机制。这蛋白酶体抑制剂、硼替佐米和 E3 泛素连接酶胶治疗以下疾病的临床成功血液疾病使泛素途径成为癌症治疗的真正靶点。因此，定义新型 E3 连接酶如何在分子水平发挥作用并研究它们在炎症中的作用至关重要以开发更具体的治疗途径。