Human Acute Myeloid Leukemia Stem Cells

人急性髓系白血病干细胞

• 批准号: 10028147
• 负责人: Ravindra Majeti
• 金额: $ 36.62万
• 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/10028147
• 关键词: Acute Myelocytic Leukemia; Address; Adult; Affect; Allogenic; Apoptosis; Architecture; Biological; Biology; Blast Cell; Bone Marrow; CD34 gene; Cell Cycle; Cell physiology; Cell surface; Cells; 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; chemotherapy; 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 model; stem cell population; 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.

项目总结