Human Acute Myeloid Leukemia Stem Cells

人急性髓系白血病干细胞

• 批准号: 10437694
• 负责人: Ravindra Majeti
• 金额: $ 35.92万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-07 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10437694
• 关键词: Acute Myelocytic Leukemia; Address; Adult; Affect; Allogenic; Apoptosis; Architecture; Biological; Biology; Blast Cell; Bone Marrow; CD34 gene; Cell Cycle; Cell surface; Cells; Chemoresistance; Clinical; Complex; Cytometry; Development; Disease; Disease remission; Drug Efflux; Exhibits; Frequencies; Gene Expression Profile; Gene Frequency; Genes; Genomics; Heterogeneity; High Dose Chemotherapy; Human; Immunodeficient Mouse; Investigation; Leukemic Cell; Malignant Neoplasms; Maps; Measurable; Methods; Minor; Modeling; Mutation; Myeloid Cells; Outcome; Pathogenesis; Pathway interactions; Patients; Population; Property; Proteomics; Recording of previous events; Recurrent disease; Refractory; Regulation; Relapse; Residual Tumors; Resistance; Role; Therapeutic; Transplantation; United States; Xenograft procedure; acute myeloid leukemia cell; aggressive therapy; base; cancer stem cell; cellular targeting; clinical remission; clinically significant; cohort; conventional therapy; curative treatments; hematopoietic cell transplantation; human old age (65+); in silico; leukemia; leukemic stem cell; novel; overexpression; prognostic; programs; self-renewal; standard of care; stem cell biology; stem cell function; stem cell model; stem cell population; stem cell self renewal; subclonal heterogeneity; therapeutic target; transcriptomics; treatment response

PROJECT SUMMARY Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow characterized by the accumulation of immature myeloid cells defective in their maturation and function. AML affects more than 20,000 adults annually in the United States, most of them over the age of 65. Even with aggressive treatments, five-year overall survival is between 30-40%, and much lower for those over age 65. Human AML shows evidence of a hierarchical cellular organization, with a minor fraction of self-renewing leukemia stem cells (LSCs) at the apex of this hierarchy. LSCs are defined as cells that are capable of initiating the disease when transplanted into immunodeficient mice and can both self-renew by giving rise to leukemia upon serial transplantation and also partially differentiate into non-LSC bulk blasts that are unable to self-renew. The clinical significance of this leukemia stem cell model is supported by the finding that gene expression signatures of AML LSCs are independently correlated with adverse clinical outcomes. Detailed characterization of AML LSCs has demonstrated their properties of self-renewal, relative quiescence, resistance to apoptosis, and increased drug efflux that likely render them less susceptible to conventional therapies aimed at the bulk proliferative disease. Thus, the generally poor clinical outcomes in AML are attributed to chemotherapy- resistant LSCs that persist during clinical remission, eventually giving rise to relapsed disease. From a therapeutic perspective, this cancer stem cell model implies that in order to eradicate the disease and achieve long-term remissions, treatment approaches must eliminate the LSC population. Although initially described several decades ago, AML LSCs have not been rigorously purified primarily due to the extensive heterogeneity of primary human AML and limitations of available xenotransplantation models. Functional LSCs have been found to be enriched in the CD34+CD38- fraction of leukemic cells, but are also present in other immunophenotypic populations. A number of cell surface markers have been characterized on these AML LSC-enriched fractions, but none are specific for LSCs or facilitate their rigorous purification. These results have made it difficult to further characterize LSC biology and to develop methods for more specific therapeutic targeting. While the field of human AML LSCs has a rich history of investigation, many key questions remain to be addressed. Can LSCs be more rigorously identified and isolated based on cell surface marker expression? What features or programs of LSCs are associated with clinical outcomes? How do adversely prognostic LSC- associated genes regulate LSC functions? Do non-LSC blasts affect the properties of LSCs? Do AML subpopulation dynamics affect LSC properties? This proposal seeks to address these questions through the investigation of human AML LSCs based on the hypothesis that LSCs exhibit distinct functional properties and biological programs that contribute to AML pathogenesis, response to therapy, and clinical outcomes. Therefore, these LSCs represent the critical cellular target for the development of curative therapies.

项目总结 急性髓系白血病(AML)是一种侵袭性的骨髓恶性肿瘤，其特征是 未成熟的髓系细胞堆积，其成熟和功能有缺陷。AML影响的不仅仅是 美国每年有2万名成年人，其中大多数是65岁以上的人。即使进行了积极的治疗， 五年总存活率在30%-40%之间，65岁以上的人的存活率要低得多。人类急性髓细胞白血病显示 具有少量可自我更新的白血病干细胞的分层细胞组织的证据 (LSC)位于此层次结构的顶端。LSCs被定义为能够在以下情况下启动疾病的细胞 移植到免疫缺陷小鼠体内，并能通过一系列引起白血病的自我更新 并部分分化为不能自我更新的非LSC成块原始细胞。这个 这一白血病干细胞模型的临床意义得到了基因表达的支持 AML LSCs的特征与不良临床结局独立相关。详细描述 AML LSCs具有自我更新、相对静止、抗凋亡等特性。 以及药物外流增加，可能会使他们不太容易受到针对大部分患者的传统疗法的影响 增殖性疾病。因此，急性髓细胞白血病的临床结果普遍较差，归因于化疗- 耐药的LSCs在临床缓解期间持续存在，最终导致复发疾病。从一个 从治疗的角度来看，这种癌症干细胞模型意味着为了根除这种疾病并实现 为了长期缓解，治疗方法必须消除LSC人口。尽管最初描述了 几十年前，由于广泛的异质性，AML LSCs还没有得到严格的纯化 原发人类急性髓系白血病和现有异种移植模型的局限性。功能正常的LSC已经 发现在白血病细胞的CD34+CD38-部分中富含，但也存在于其他 免疫表型群体。在这些AML上已经鉴定了许多细胞表面标记 LSC富集组分，但没有一种是LSC所特有的，也没有一种能促进LSC的严格纯化。这些结果 使得进一步描述LSC的生物学特性和开发更具体的治疗方法变得困难 瞄准目标。虽然人类急性髓系白血病干细胞领域有着丰富的研究历史，但仍有许多关键问题有待解决 被称呼为。能否根据细胞表面标志物的表达更严格地鉴定和分离LSC？ LSCs的哪些特征或程序与临床结果相关？如何预测不利的LSC- 相关基因调控LSC功能？非LSC爆炸是否会影响LSC的属性？做AML 子种群动态会影响LSC特性吗？这项提案试图通过 基于以下假设的人急性髓系白血病LSCs的研究：LSCs具有独特的功能特性和 有助于AML发病机制、治疗反应和临床结果的生物学程序。 因此，这些LSCs是开发治疗方法的关键细胞靶点。