A Novel E3 Ubiquitin Ligase for CML Stem Cells

用于 CML 干细胞的新型 E3 泛素连接酶

基本信息

批准号：
9810513
负责人：
WENYONG CHEN
金额：
$ 22.58万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9810513
关键词：
Address Aging Amino Acids Apoptosis Bcr-Abl tyrosine kinase Biogenesis Cell Aging Cell Count Cell Culture Techniques Cell Cycle Cell Cycle Regulation Cell Maintenance Cell Survival Cell physiology Cells Chronic Myeloid Leukemia DNA Damage DNA Repair Gene Deacetylase Dependence Development Disease Drug resistance Exhibits Financial Hardship Gene Expression Gene Family Generations Genes Genetic Goals Health Hematology Hematopoietic stem cells Human Imatinib Knock-out Leukemic Cell Life Malignant Neoplasms Mus Natural Immunity Oncogenic Output Oxidative Stress Pathway interactions Patients Pharmaceutical Preparations Protein Biosynthesis Proteins Proteomics Recurrent disease Refractory Regimen Regulation Research Ribosomes Risk Role SIRT1 gene Safety Stable Isotope Labeling Stem cells Survivors Testing Therapeutic Tyrosine Kinase Inhibitor Ubiquitin Ubiquitination bcr-abl Fusion Proteins cell growth chronic myeloid leukemia cell design functional decline improved insight knock-down leukemia leukemia treatment leukemic stem cell mouse development mouse model new therapeutic target non-compliance novel novel strategies overexpression pleiotropism prevent self-renewal side effect stem success therapeutic target ubiquitin-protein ligase

项目摘要

Project Summary Chronic myeloid leukemia (CML) is a lethal malignancy. Today, tyrosine kinase inhibitors (TKIs) effectively treat the disease, leading to rapid expansion of long-term CML survivors. However, TKIs fail to eradicate CML leukemia stem cells (LSCs) and the disease relapses when the drug is stopped. As a result, CML patients need life-long dependence on TKIs. There is a need to eradicate CML LSCs for a cure. Our long-term goal is to understand the mechanisms of CML LSC drug resistance, and to develop novel strategies to eradicate CML LSCs and improve CML treatment. We have previously shown that protein deacetylase SIRT1 is activated by BCR-ABL transformation and promotes CML progression and LSC drug resistance. In our recent study of hematopoietic stem cell (HSC) aging, we identified an E3 ubiquitin ligase Trim26 as a novel Sirt1 effector in old mouse HSCs. We found that Trim26 inhibition had strikingly similar effect to SIRT1 inhibition on suppressing CML cell growth and survival. Trim26 was over-expressed in both human and mouse CML progenitor cells, and Trim26 knockout reduced CML LSCs. Unlike Sirt1 knockout, Trim26 knockout did not affect normal mouse development and functions. The objective of this application is to determine the roles of Trim26 in regulating CML LSC survival and self-renewal. Our central hypothesis is that Trim26 promotes CML LSC survival and maintenance and facilitates leukemia development. The rationale for the proposed research is that better understanding the roles of Trim26 in CML LSCs will help design a more effective and safer strategy to eradicate CML LSCs and bring a cure to the disease. We will test our central hypothesis in two specific aims: 1) To determine the role of Trim26 in CML LSC survival and self-renewal; 2) To determine the mechanisms of Trim26 in regulating CML LSCs. Under aim 1, the effect of Trim26 knockout on CML LSC survival and maintenance as well as the LSC persistence upon TKI treatment will be determined using a mouse model of CML. Under aim 2, the requirement of Trim26 E3 ubiquitin ligase activity for LSC functions and CML development, and novel ubiquitination substrates of Trim26 will be determined for regulation of CML LSC functions and leukemia development. The proposed research is significant because it will reveal a new mechanism of CML LSC survival and drug resistance, and identify Trim26 as a novel and safe therapeutic target to eradicate CML LSCs.

项目摘要慢性髓样白血病（CML）是致命的恶性肿瘤。如今，有效地有效地酪氨酸激酶抑制剂（TKIS）治疗该疾病，导致长期CML幸存者的快速扩张。但是，TKI无法消除CML 停止药物时，白血病干细胞（LSC）和疾病复发。结果，CML患者需要终身对TKIS的依赖。需要根除CML LSC来治愈。我们的长期目标是了解CML LSC耐药性的机制，并制定消除CML的新型策略 LSC并改善CML处理。我们先前已经表明蛋白质脱乙酰基酶SIRT1被激活 BCR-ABL转化并促进CML进展和LSC耐药性。在我们最近的研究中造血干细胞（HSC）衰老，我们识别出E3泛素连接酶TRIM26是旧的SIRT1效应器鼠标HSC。我们发现TRIM26抑制作用与SIRT1抑制作用非常相似 CML细胞生长和生存。 TRIM26在人和小鼠CML祖细胞中都过表达，和TRIM26敲除减少了CML LSC。与SIRT1淘汰赛不同，TRIM26敲除不会影响正常鼠标发展和功能。该应用的目的是确定Trim26在调节中的作用 CML LSC生存和自我更新。我们的中心假设是TRIM26促进CML LSC存活和维持和促进白血病的发展。拟议研究的理由是更好了解TRIM26在CML LSC中的作用将有助于设计更有效，更安全的策略消除CML LSC并为该疾病提供治疗。我们将以两个具体的目的测试中心假设： 1）确定TRIM26在CML LSC存活和自我更新中的作用； 2）确定机制调节CML LSC的TRIM26。在AIM 1下，TRIM26敲除对CML LSC生存的影响和维护以及TKI治疗时的LSC持久性将使用小鼠模型确定 CML。在AIM 2下，对LSC功能和CML的TRIM26 E3泛素连接酶活性的要求将确定TRIM26的开发和新型的泛素化底物，以调节CML LSC 功能和白血病的发展。拟议的研究很重要，因为它将揭示一个新的 CML LSC生存和耐药性的机制，并将TRIM26识别为一种新颖且安全的治疗目标根除CML LSC。