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

项目摘要 慢性淋巴细胞白血病（CLL）是美国最常见的成人白血病。的 疾病的特征在于血液中异常的CD 5 +/CD 19 + 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是不可治愈的。虽然目前的 治疗增加了总体CLL长期生存，复发和疾病抵抗经常发生。 目前，CLL的细胞起源尚不清楚，因此难以确定复发的原因。传统上， B细胞的成熟亚群--如边缘和记忆B细胞--被怀疑是 起源疾病范例传统上认为干细胞和祖细胞不参与免疫调节。 发病机理然而，最近发表的观察表明，CLL可能起源于 早期造血干细胞（HSC）。来自CLL患者的HSC已被证明可以形成 当在小鼠中生长时，CD5 +/CD19 + B细胞异常。这些CLL HSC的单细胞基因分析显示， 与来自正常健康对照的HSC相比，转录因子-GATA 2-的过表达。GATA2是 在HSC的发育和生长中至关重要，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，异常干细胞负责治疗 抵抗和复发。目前的CLL医学治疗集中于靶向成熟的癌性B细胞。 然而，这种策略并不是针对造血干细胞的，我认为这一群体可能 有助于疾病复发和治疗抗性。在这个建议中，我试图更好地理解CLL 通过首先确定HSC在CLL发展中的作用，其次通过研究GATA 2的 在正常和CLL患者来源的HSC中的功能。我假设CLL患者来源的HSC是 白血病起始细胞和白血病起始依赖于GATA2信号传导。成功完成 该项目将确定CLL HSC在CLL发展中的作用，并将指导新的治疗方法， CLL。这也将使我发展独特的技术，批判性思维和有效的沟通技巧 这对我将来成为独立调查员的目标至关重要。

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.