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.