A Paradigm Shift in Chronic Lymphocytic Leukemia: Defining the Role of Hematopoietic Stem Cells in Leukemogenesis

慢性淋巴细胞白血病的范式转变：定义造血干细胞在白血病发生中的作用

• 批准号: 10161747
• 负责人: Eileen Yifan Hu
• 金额: $ 5.1万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10161747
• 关键词: Acute Myelocytic Leukemia; Affect; Agreement; Area; Automobile Driving; B-Lymphocyte Subsets; B-Lymphocytes; Biological Assay; Blood; Bone Marrow; Bone Marrow Transplantation; CD19 gene; CD34 gene; Cancerous; Cells; Chronic; Chronic Lymphocytic Leukemia; Communication; Critical Thinking; Cytometry; Data; Development; Disease; Disease Resistance; Drug resistance; Engraftment; Event; Future; GATA2 transcription factor; Generations; Genes; Goals; Growth and Development function; Hematologic Neoplasms; Hematological Disease; Hematopoiesis; Hematopoietic stem cells; Immunocompromised Host; Immunodeficient Mouse; In Vitro; Lead; Leukemic Cell; Leukemic Hematopoietic Stem Cell; Lymphoid; Lymphoid Cell; Lymphopoiesis; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mature B-Lymphocyte; Medical; Memory B-Lymphocyte; Messenger RNA; Monitor; Mus; Mutate; Mutation; Myelopoiesis; Natural regeneration; Oncogenic; Pathogenesis; Patients; Play; Population; Property; Proteins; Publishing; Recurrent disease; Relapse; Reporting; Research Personnel; Resistance; Role; Signal Transduction; Solid; Somatic Mutation; Therapeutic; Time; United States; adult leukemia; cancer cell; chronic lymphocytic leukemia cell; curative treatments; in vivo; knock-down; leukemia; leukemia initiating cell; leukemic stem cell; leukemogenesis; lymphoid organ; new therapeutic target; novel; overexpression; progenitor; self-renewal; skills; stem cells; theories; traditional therapy

PROJECT SUMMARY Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the United States. The disease is characterized by the proliferation and accumulation of abnormal CD5+/CD19+ B cells in the blood and lymphoid organs. CLL is considered incurable aside from bone marrow transplantation. Although current therapies have increased overall CLL long-term survival, relapse and disease resistance often occur. Currently, the cellular origin of CLL is unknown, making it difficult to identify the cause of relapse. Classically, mature subsets of B cells - such as marginal and memory B cells - are suspected to be the populations of origin. The disease paradigm has traditionally assumed that stem and progenitor cells are non-participatory in disease pathogenesis. However, recent published observations suggest that CLL may originate from populations of early hematopoietic stem cells (HSC). HSCs from CLL patients have been shown to form abnormal CD5+/CD19+ B cells when grown in mice. Single-cell gene analyses of these CLL HSCs show overexpression of a transcription factor - GATA2 - compared to HSCs from normal healthy controls. GATA2 is critical in the development and growth of HSCs but its role in CLL and lymphopoiesis has not been studied. In other solid and hematological malignancies, abnormal stem cells are responsible for therapy resistance and relapse. Current CLL medical therapy focuses on targeting the mature cancerous B cells. However, this strategy is not designed to target hematopoietic stem cells—a population that I propose may contribute to disease relapse and therapy resistance. In this proposal, I seek to better understand CLL pathogenesis by first determining the role of HSCs in CLL development and second by investigating GATA2's function in both normal and CLL patient-derived HSCs. I hypothesize that CLL patient-derived HSCs are leukemia-initiating cells and that leukemia initiation depends on GATA2 signaling. Successful completion of this project will define the role of CLL HSCs in CLL development and would direct new curative therapies in CLL. It will also allow me to develop unique technical, critical thinking, and effective communication skills crucial to my goals of becoming an independent investigator in the future.

项目摘要 慢性淋巴细胞白血病（CLL）是美国最常见的成年白血病。这 疾病的特征是血液中异常CD5+/CD19+ B细胞的增殖和积累 和淋巴器官。除了骨髓移植外，CLL被认为无法治愈。虽然是最新的 疗法经常会增加总体CLL长期生存，缓解和抗病性。 当前，CLL的细胞起源尚不清楚，因此难以识别救济原因。经典， B细胞的成熟子集（例如边际和记忆B细胞）被怀疑是 起源。疾病范式传统上认为茎和祖细胞在 疾病发病机理。但是，最近发表的观察结果表明CLL可能起源于 早期造血干细胞（HSC）的种群。已显示来自CLL患者的HSC形成 在小鼠中生长时，异常的CD5+/CD19+ B细胞。这些CLL HSC的单细胞基因分析显示 与正常健康对照的HSC相比，转录因子的过表达 - GATA2-。 GATA2是 HSC的发展和增长至关重要，但其在CLL和淋巴细胞中的作用尚未研究。 在其他固体和血液系统恶性肿瘤中，异常干细胞负责治疗 抵抗和复发。当前的CLL药物治疗侧重于靶向成熟的癌性B细胞。 但是，该策略并非旨在针对造血干细胞，我建议的人群可能 有助于疾病缓解和抗药性。在此提案中，我试图更好地了解CLL 通过首先确定HSC在CLL发育中的作用，其次通过研究GATA2的作用 在正常和CLL患者衍生的HSC中的功能。我假设CLL患者衍生的HSC是 白血病发射细胞和白血病倡议取决于GATA2信号传导。成功完成 该项目将定义CLL HSC在CLL开发中的作用，并将指导新的治疗疗法 Cll。这也将使我能够发展独特的技术，批判性思维和有效的沟通技巧 对于我将来成为独立研究者的目标至关重要。