Human Acute Myeloid Leukemia Stem Cells

人急性髓系白血病干细胞

• 批准号: 10212356
• 负责人: Ravindra Majeti
• 金额: $ 36.64万
• 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/10212356
• 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; response; 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

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.

项目概要 急性髓系白血病 (AML) 是一种侵袭性骨髓恶性肿瘤，其特征为 成熟和功能有缺陷的未成熟骨髓细胞的积累。 AML 影响超过 美国每年有 20,000 名成年人，其中大多数年龄超过 65 岁。即使采取积极的治疗， 五年总生存率在 30-40% 之间，对于 65 岁以上的人来说要低得多。人类 AML 显示 分层细胞组织的证据，其中有一小部分自我更新的白血病干细胞 （LSC）位于该层次结构的顶端。 LSC 被定义为在以下情况下能够引发疾病的细胞： 移植到免疫缺陷小鼠体内，可以自我更新，在连续注射后引起白血病 移植并部分分化为无法自我更新的非 LSC 大量母细胞。这 基因表达的发现支持了这种白血病干细胞模型的临床意义 AML LSC 的特征与不良临床结果独立相关。详细表征 AML LSCs 已证明其具有自我更新、相对静止、抗凋亡等特性 以及增加的药物流出可能使他们不太容易受到针对大众的传统疗法的影响 增殖性疾病。因此，AML 临床结果普遍较差归因于化疗—— 耐药LSC在临床缓解期间持续存在，最终导致疾病复发。来自一个 从治疗的角度来看，这种癌症干细胞模型意味着，为了根除疾病并实现 为了实现长期缓解，治疗方法必须消除 LSC 群体。虽然最初描述 几十年前，AML LSC 尚未经过严格纯化，主要是由于广泛的异质性 原发性人类 AML 的研究和现有异种移植模型的局限性。功能性 LSC 已 发现在白血病细胞的 CD34+CD38- 部分富集，但也存在于其他细胞中 免疫表型群体。许多细胞表面标记物已在这些 AML 上得到表征 富含 LSC 的级分，但没有一种对 LSC 具有特异性，也没有利于其严格纯化。这些结果 使得进一步表征 LSC 生物学特征和开发更具体的治疗方法变得困难 瞄准。虽然人类 AML LSC 领域有着丰富的研究历史，但许多关键问题仍然有待解决。 得到解决。能否根据细胞表面标志物表达更严格地鉴定和分离 LSC？ LSC 的哪些特征或程序与临床结果相关？ LSC-不良预后如何 相关基因调节LSC功能？非 LSC 爆炸是否会影响 LSC 的特性？进行反洗钱 亚群动态会影响 LSC 特性吗？该提案旨在通过 基于 LSC 表现出独特功能特性的假设和对人类 AML LSC 的研究 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 LSC 代表了治疗疗法开发的关键细胞靶点。