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: 9212638
• 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/9212638
• 关键词: Acute; Address; Adverse effects; Alprostadil; Animals; Blood; Bone Marrow Transplantation; Cell Nucleus; Cellular biology; Chronic Myeloid Leukemia; Clinical; 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; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Herbicides; Human; In Vitro; Intrinsic factor; Knowledge; Leukemic 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; TCF Transcription Factor; 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; protein B; public health relevance; reconstitution; regenerative therapy; self-renewal; small molecule; 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的独特能力负责维持终生 产生多个血统和HSC移植是最广泛部署的再生疗法。另一方面，LSC负责各种白血病的启动，维护和传播。治愈白血病取决于有效地通过常规化学疗法或放射疗法有效地放射白血病细胞后的放射性LSC的能力。因此，必须需要深入了解HSC和LSC自我更新如何受到内在和环境因素的调节。 Wnt蛋白或前列腺素E2（PGE2）可以引起β-catenin的激活，其在HSC和LSC中的作用仍然是一个广泛的争论问题。众所周知，活化的β-catenin转移到核与TCF/LEF转录因子相互作用的核中，到目前为止，很少有信息如何将β-catenin活性与转录程序变化连接在一起。基于我们对TCF1和LEF1的重点分析，我们假设TCF/LEF和β/γ-catenin蛋白构成了HSC中的不同调节模块，并且它们各自的转录程序是消除LSC的热目标。在以下两个目标中，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PGE1在靶向LSC中的有益作用，如下图所述。具体目的1。剖析HSC和LSC中TCF3/TCF4和β/γ-catenin模块的作用。具体目标2。研究PGE1治疗CML的治疗益处。退伍军人增加了对有害环境的接触，例如除草剂，这些环境与白血病风险增加有关。我们提出的研究直接解决了需要白血病治疗和血液重构的退伍军人的需求。通过全面解剖TCF/LEF和β/γ-catenin在HSC中的调节作用，我们将获得基本知识，有助于提高骨髓移植的效率。通过研究使用TCF/LEF-和β/γ-catenin依赖性转录程序作为LSC中的可药物靶标的概念，我们希望设计新的疗法来治疗CML和其他血液系统恶性肿瘤。这些研究来自基本和转化方面，将有助于实现再生医学中干细胞的希望，改善 血液系统恶性肿瘤的预后，并增强了退伍军人的医疗保健。