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.

项目摘要 急性髓样白血病（AML）是骨髓的侵略性恶性肿瘤，其特征是 未成熟的髓样细胞的积累在其成熟和功能中有缺陷。 AML的影响超过 美国每年有20,000名成年人，其中大多数65岁以上。即使接受激进的治疗， 五年的总生存率在30-40％之间，而65岁以上的人则低得多。人AML显示 分层细胞组织的证据，其自我更新白血病干细胞的一小部分 （LSC）在此层次结构的顶点。 LSC被定义为能够在 移植到免疫缺陷的小鼠中，可以通过在系列时引起白血病来自我更新 移植，也部分区分为无法自我更新的非LSC散装爆炸。这 该白血病干细胞模型的临床意义得到了基因表达的发现支持 AML LSC的特征与不良临床结果独立相关。详细的特征 AML LSC的自我更新，相对静止，对凋亡的抗性的特性， 并增加了药物外排，这可能会使它们不易受到针对大量的常规疗法的影响 增殖性疾病。因此，AML中通常较差的临床结果归因于化学疗法 - 在临床缓解过程中持续存在的耐药性LSC，最终导致复发性疾病。来自 治疗性的观点，这种癌症干细胞模型暗示，为了消除疾病并实现 长期恢复，治疗方法必须消除LSC人群。尽管最初描述了 几十年前，AML LSC并未严格纯化，这主要是由于广泛的异质性 原代人AML和可用的异种移植模型的局限性。功能性LSC已经 发现在白血病细胞的CD34+CD38-富集中富集，但也存在于其他 免疫表型人群。这些AML已经表征了许多细胞表面标记 富含LSC的馏分，但没有特定于LSC或促进其严格的纯化。这些结果 很难进一步表征LSC生物学并开发用于更具体治疗的方法 定位。尽管人类AML LSC的领域具有丰富的调查历史，但仍有许多关键问题 被解决。可以根据细胞表面标记表达更严格地识别和分离LSC？ LSC的哪些功能或程序与临床结果有关？如何不利的预后LSC- 相关基因调节LSC功能？非LSC爆炸会影响LSC的性质吗？做AML 亚种群动态会影响LSC属性？该建议旨在通过 基于LSC表现出不同功能特性和 有助于AML发病机理，对治疗的反应和临床结果的生物学计划。 因此，这些LSC代表了治愈疗法开发的关键细胞靶标。