Targeting Tcf/Lef-transcriptional program in leukemic stem cells

靶向白血病干细胞中的 Tcf/Lef 转录程序

• 批准号: 9022091
• 负责人: Hai-Hui Xue
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9022091
• 关键词: Acute; Address; Adverse effects; Alprostadil; Animals; Blood; Bone Marrow Transplantation; Cell Nucleus; Chronic Myeloid Leukemia; Cytosol; Dinoprostone; Disease remission; Dissection; Environment; Environmental Risk Factor; Exposure to; FDA approved; Family; Financial compensation; Gene Expression; Genes; Genetic Transcription; Healthcare; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Herbicides; Human; In Vitro; Intrinsic factor; Knowledge; Leukemic Cell; Leukemic Hematopoietic Stem Cell; Link; Maintenance; Molecular; Mouse Strains; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pre-Clinical Model; Production; Proteins; Radiation therapy; Regenerative Medicine; Relapse; Risk; Role; Stem cells; Testing; Therapeutic; Therapeutic Effect; Tumor Debulking; Veterans; Wnt proteins; Xenograft Model; base; beta catenin; chemotherapy; clinical practice; improved; in vivo; leukemia; leukemia treatment; leukemic stem cell; member; mouse model; novel; novel therapeutics; outcome forecast; programs; public health relevance; reconstitution; regenerative therapy; self-renewal; small molecule; stem cell biology; therapeutic target; tool; transcription factor; transcriptome

 DESCRIPTION (provided by applicant): Hematopoietic and leukemic stem cells (HSCs and LSCs, respectively) are endowed with unlimited self-renewal capacity. This unique ability of HSCs is responsible for sustaining lifetime production of multiple blood lineages, and HSC transplantation represents the most widely deployed regenerative therapy. On the other hand, LSCs are responsible for initiation, maintenance, and propagation of various types of leukemia. A cure for leukemia depends on the ability to eradicate LSCs after effective debulking of leukemic cells with conventional chemo- or radiotherapy. Therefore, there are imperative needs to seek in-depth understanding of how HSC and LSC self-renewal is regulated by intrinsic and environmental factors. β-catenin activation can be elicited by Wnt proteins or prostaglandin E2 (PGE2), and its roles in HSCs and LSCs remain an extensively debated issue. It is known that activated β-catenin translocate into the nucleus where it interacts with Tcf/Lef transcription factors, thus far there is little informationon how β- catenin activity is connected to transcriptional program changes. Based on our focused analysis on Tcf1 and Lef1, we hypothesize that Tcf/Lef and β/γ-catenin proteins constitute distinct regulatory modules in HSCs, and their respective transcriptional programs are therapeutic targets for eradicating LSCs. In the following 2 aims, we seek to systematically elucidate distinct roles of each module in HSC biology and mechanistically assess beneficial roles of PGE1 in targeting LSCs, as outlined in the figure below. Specific Aim 1. To dissect the roles of Tcf3/Tcf4 and β/γ-catenin modules in HSCs and LSCs. Specific Aim 2. To investigate the therapeutic benefits of PGE1 in treating CML. Veterans have increased exposure to harmful environments, such as herbicides, which link to increased risk of leukemia's. Our proposed study directly addresses the needs for veterans who require leukemia treatment and blood reconstitution. Through comprehensive dissection of the regulatory roles of Tcf/Lef and β/γ-catenin in HSCs, we will acquire essential knowledge that helps improve the efficacy of bone marrow transplantation. By delving into the concept of using Tcf/Lef- and β/γ-catenin-dependent transcriptional programs as druggable targets in LSCs, we expect to devise novel therapies to treat CML and other hematological malignancies. These studies, from both basic and translational fronts, will help realize the promise of stem cells in regenerative medicine, improve the prognosis of hematological malignancies, and enhance the healthcare for veterans.

 描述（由申请人提供）： 造血干细胞和白血病干细胞（分别为HSC和LSC）具有无限的自我更新能力。HSC的这种独特能力是维持生命的关键。 造血干细胞移植是多种血液谱系的产生，而HSC移植代表了最广泛使用的再生疗法。另一方面，LSC负责各种类型白血病的起始、维持和增殖。白血病的治愈取决于在用常规化疗或放疗有效减积白血病细胞后根除LSC的能力。因此，迫切需要寻求深入了解HSC和LSC自我更新是如何由内在和环境因素调节的。 β-catenin的激活可以由Wnt蛋白或前列腺素E2（PGE 2）引起，其在HSC和LSC中的作用仍然是一个广泛争论的问题。已知激活的β-catenin转位到细胞核中，在那里它与Tcf/Lef转录因子相互作用，但目前关于β- catenin的活性如何与转录程序的改变联系的信息很少。基于我们对Tcf 1和Lef 1的集中分析，我们假设Tcf/Lef和β/γ-catenin蛋白在HSC中构成不同的调控模块，并且它们各自的转录程序是根除LSC的治疗靶点。在以下2个目标中，我们试图系统地阐明每个模块在HSC生物学中的不同作用，并机械地评估PGE 1在靶向LSC中的有益作用，如下图所示。具体目标1。探讨Tcf 3/Tcf 4和β/γ-catenin模块在HSC和LSCs中的作用。具体目标2。探讨前列腺素E1（PGE 1）治疗慢性粒细胞白血病（CML）的疗效。 退伍军人接触有害环境的机会增加，如除草剂，这与白血病的风险增加有关。我们提出的研究直接解决了需要白血病治疗和血液重建的退伍军人的需求。通过对Tcf/Lef和β/γ-catenin在造血干细胞中的调控作用的全面剖析，我们将获得有助于提高骨髓移植疗效的基本知识。通过深入研究使用Tcf/Lef-和β/γ-连环蛋白依赖性转录程序作为LSC中的药物靶点的概念，我们期望设计新的疗法来治疗CML和其他血液恶性肿瘤。这些研究，从基础和转化方面，将有助于实现干细胞在再生医学中的前景，改善 血液恶性肿瘤的预后，并加强退伍军人的保健。