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）： 造血干细胞和白血病干细胞（分别为 HSC 和 LSC）被赋予无限的自我更新能力，HSC 的这种独特能力负责维持生命。 另一方面，LSC 负责多种类型白血病的发生、维持和传播，而 HSC 移植则取决于在发生后根除 LSC 的能力。因此，迫切需要深入了解 HSC 和 LSC 的自我更新如何受到内在和环境因素的调节。 β-连环蛋白激活可由 Wnt 蛋白或前列腺素 E2 (PGE2) 引起，其在 HSC 和 LSC 中的作用仍然是一个备受争议的问题。众所周知，激活的 β-连环蛋白易位到细胞核中，与 Tcf/Lef 转录相互作用。因素，到目前为止，关于 β-连环蛋白活性如何与转录程序变化相关的信息很少。根据我们对 Tcf1 和 Lef1 的集中分析，我们捕获了 Tcf/Lef 和。 β/γ-连环蛋白构成 HSC 中不同的调节模块，其各自的转录程序是根除 LSC 的治疗靶标。在以下两个目标中，我们力求系统地阐明每个模块在 HSC 生物学中的不同作用，并从机制上评估其有益作用。 PGE1 在靶向 LSC 中的作用，如下图所示。 具体目标 1. 剖析 Tcf3/Tcf4 和 β/γ-连环蛋白模块在 HSC 和中的作用。 LSC. 具体目标 2. PGE1 在治疗 CML 方面的治疗效果 退伍军人接触有害环境的情况增加，例如除草剂，这与白血病风险增加有关。通过全面剖析 Tcf/Lef 和 β/γ-catenin 在 HSC 中的调节作用，我们将获得有助于提高骨髓移植疗效的重要知识。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 中的药物靶标的概念，我们期望从基础和转化两个方面设计出治疗 CML 和其他血液恶性肿瘤的新疗法。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，并加强退伍军人的医疗保健。