A Novel E3 Ubiquitin Ligase for CML Stem Cells

用于 CML 干细胞的新型 E3 泛素连接酶

• 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
• 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

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 慢性粒细胞白血病（CML）是一种致命的恶性肿瘤。今天，酪氨酸激酶抑制剂（TKI）有效地 治疗这种疾病，导致慢性粒细胞白血病长期幸存者的迅速扩大。然而，TKI未能根除CML 白血病干细胞（LSC）和疾病复发时，药物停止。因此，CML患者 需要终生依赖TKI需要根除CML LSC以治愈。我们的长期目标是 了解CML LSC耐药的机制，并开发根除CML的新策略 LSC和改善CML治疗。我们以前已经证明，蛋白质脱乙酰酶SIRT 1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， 为了研究造血干细胞（HSC）衰老，我们鉴定了一种E3泛素连接酶Trim 26作为老年人中一种新的Sirt 1效应子。 小鼠HSC。我们发现Trim 26抑制与SIRT 1抑制在抑制细胞凋亡方面具有惊人相似的效果。 CML细胞生长和存活。Trim 26在人和小鼠CML祖细胞中都过表达， 和Trim 26敲除减少的CML LSC。与Sirt 1基因敲除不同，Trim 26基因敲除对正常小鼠无影响 发展和功能。本申请的目的是确定Trim 26在调节 CML LSC存活和自我更新。我们的中心假设是Trim 26促进CML LSC存活， 维持并促进白血病发展。这项研究的基本原理是， 了解Trim 26在CML LSC中的作用将有助于设计更有效、更安全的策略， 根除CML LSC并治愈疾病。我们将在两个具体目标中检验我们的中心假设： 1)确定Trim 26在CML LSC存活和自我更新中的作用; 2）确定Trim 26在CML LSC存活和自我更新中的作用机制。 Trim 26在调节CML LSC中的作用在目标1下，Trim 26敲除对CML LSC存活和CML LSC死亡的影响是显著的。 TKI治疗后的LSC维持以及LSC持续性将使用以下小鼠模型来确定： 慢粒。在目标2下，Trim 26 E3泛素连接酶活性对于LSC功能和CML的需求是必需的。 Trim 26的新型泛素化底物将被确定用于调节CML LSC。 功能和白血病的发展。这项拟议中的研究意义重大，因为它将揭示一种新的 CML LSC存活和耐药性的机制，并将Trim 26确定为一种新型安全的治疗药物。 以根除CML LSC为目标。