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.

项目总结 慢性淋巴细胞白血病(CLL)是美国最常见的成人白血病。这个 疾病的特征是血液中异常的CD5+/CD19+B细胞的增殖和积聚 和淋巴器官。除骨髓移植外，慢性淋巴细胞性白血病被认为是无法治愈的。虽然是当前的 治疗提高了慢性淋巴细胞性白血病的整体长期存活率，复发和抗药性经常发生。 目前，CLL的细胞起源尚不清楚，因此很难确定复发的原因。经典的是， 成熟的B细胞亚群--如边缘和记忆性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是非参与性的 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。来自慢性淋巴细胞性白血病患者的造血干细胞已被证明形成 在小鼠体内生长时CD5+/CD19+B细胞异常。对这些CLL造血干细胞的单细胞基因分析显示 转录因子GATA2的过度表达与正常健康对照组的HSCs相比。GATA2是 在HSCs的发育和生长中起关键作用，但其在CLL和淋巴生成中的作用尚未被研究。 在其他实体和血液系统的恶性肿瘤中，异常干细胞负责治疗。 抵抗和复发。目前的CLL药物治疗主要针对成熟的癌性B细胞。 然而，这一策略并不是针对造血干细胞而设计的--我建议这一群体可能 有助于疾病复发和治疗抵抗。在这项建议中，我试图更好地理解CLL 致病机制：首先确定HSCs在CLL发育中的作用，其次通过研究GATA2‘S 在正常和慢性淋巴细胞性白血病患者来源的造血干细胞中均有功能。我假设慢性淋巴细胞白血病患者来源的造血干细胞是 白血病的启动细胞，白血病的启动依赖于GATA2信号。成功完成 该项目将确定CLL造血干细胞在CLL发展中的作用，并将指导新的治疗方法 CLL.它还将使我发展独特的技术、批判性思维和有效的沟通技能 对我未来成为一名独立调查员的目标至关重要。