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: 9979623
• 负责人: Eileen Yifan Hu
• 金额: $ 5.05万
• 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/9979623
• 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.

项目概要 慢性淋巴细胞白血病（CLL）是美国最常见的成人白血病。这 该疾病的特点是血液中异常 CD5+/CD19+ B 细胞的增殖和积累 和淋巴器官。 CLL 被认为除了骨髓移植之外无法治愈。虽然目前 治疗方法提高了 CLL 的总体长期生存率，但经常发生复发和疾病抵抗。 目前，CLL 的细胞起源尚不清楚，因此很难确定复发的原因。经典地讲， 成熟的 B 细胞亚群（例如边缘 B 细胞和记忆 B 细胞）被怀疑是 起源。疾病范式传统上假设干细胞和祖细胞不参与 疾病发病机制。然而，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）群体。来自 CLL 患者的 HSC 已被证明可形成 在小鼠体内生长时出现异常的 CD5+/CD19+ B 细胞。这些 CLL HSC 的单细胞基因分析表明 与正常健康对照的 HSC 相比，转录因子 GATA2 过度表达。 GATA2 是 对 HSC 的发育和生长至关重要，但其在 CLL 和淋巴细胞生成中的作用尚未研究。 在其他实体和血液恶性肿瘤中，异常干细胞负责治疗 耐药和复发。目前 CLL 药物治疗的重点是针对成熟的癌性 B 细胞。 然而，这种策略并不是针对造血干细胞而设计的——我认为造血干细胞可能是一个群体。 导致疾病复发和治疗抵抗。在这个提案中，我寻求更好地理解 CLL 首先确定 HSC 在 CLL 发展中的作用，然后研究 GATA2 的发病机制 在正常和 CLL 患者来源的 HSC 中都有功能。我假设 CLL 患者来源的 HSC 是 白血病起始细胞，白血病起始依赖于 GATA2 信号传导。顺利完成 该项目将明确 CLL HSC 在 CLL 发展中的作用，并指导新的治疗方法 慢性淋巴细胞白血病。它还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 对我未来成为一名独立调查员的目标至关重要。