Targeting Tcf/Lef-transcriptional program in leukemic stem cells

 描述(由申请人提供)： 造血干细胞和白血病干细胞(HSCs和LSCs)具有无限的自我更新能力。造血干细胞的这种独特能力负责维持生命。 多血统的产生和造血干细胞移植是应用最广泛的再生疗法。另一方面，LSCs负责启动、维持和传播各种类型的白血病。白血病的治愈取决于用常规化疗或放射治疗有效去除白血病细胞后根除LSCs的能力。因此，迫切需要寻求深入了解HSC和LSC的自我更新是如何受到内在和环境因素的调节的。Wnt蛋白或前列腺素E_2(PGE_2)可诱导β-连环蛋白的激活，其在肝星状细胞和LSC中的作用仍是一个广泛争论的问题。已知激活的β-连环蛋白转位到细胞核内，在那里它与Tcf/Lef转录因子相互作用，到目前为止，关于β-连环蛋白活性如何与转录程序改变有关的信息很少。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HSCs中不同的调控模块，它们各自的转录程序是根除LSCs的治疗靶点。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，如下图所示。具体目的1.分析TCF3/TCF4和β/γ-catenin模块在肝星状细胞和喉鳞状细胞中的作用。具体目的2.探讨前列腺素E_1治疗慢性粒细胞白血病的疗效。退伍军人在有害环境中的暴露增加，如除草剂，这与白血病风险增加有关。我们拟议的研究直接满足了需要白血病治疗和血液重建的退伍军人的需求。通过全面剖析Tcf/LEF和β/γ-catenin在造血干细胞中的调节作用，我们将获得有助于提高骨髓移植疗效的基本知识。通过深入研究在LSC中使用Tcf/Lef和β/γ依赖的连环蛋白转录程序作为可用药靶点的概念，我们期望设计出治疗慢性粒细胞白血病和其他血液系统恶性肿瘤的新疗法。这些研究，从基础和翻译两个方面，将有助于实现干细胞在再生医学中的前景，改善 改善血液系统恶性肿瘤的预后，加强退伍军人的医疗保健。

 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.