Human Acute Myeloid Leukemia Stem Cells

项目摘要 急性髓性白血病（AML）是一种侵袭性骨髓恶性肿瘤，其特征在于： 未成熟的髓样细胞在其成熟和功能方面有缺陷的积聚。AML影响超过 美国每年有2万名成年人，其中大多数超过65岁。即使有积极的治疗， 五年总生存率在30- 40%之间，65岁以上的人更低。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）在这个层次结构的顶点。LSC被定义为能够引发疾病的细胞， 移植到免疫缺陷的小鼠中，并且都可以通过引起白血病而自我更新。 在移植中，LSC细胞可以部分分化成不能自我更新的非LSC大块原始细胞。的 该白血病干细胞模型的临床意义得到以下发现的支持： AML LSC的特征与不良临床结果独立相关。详细表征 已经证明了它们的自我更新，相对静止，抗凋亡， 增加的药物外排可能使他们对针对大部分患者的传统疗法不太敏感 增殖性疾病因此，AML的临床结局通常较差归因于化疗- 耐药LSC在临床缓解期间持续存在，最终导致疾病复发。从 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， 长期缓解，治疗方法必须消除LSC人群。虽然最初描述 几十年前，AML LSC没有被严格纯化，主要是由于广泛的异质性， 原发性人类AML的发病率和可用异种移植模型的局限性。功能性LSC已被 发现在白血病细胞的CD 34 + CD 38-部分中富集，但也存在于其他细胞中。 免疫表型群体。一些细胞表面标志物已在这些AML上进行了表征。 LSC富集的级分，但没有一个是LSC的特异性或促进其严格的纯化。这些结果 已经使得难以进一步表征LSC生物学和开发用于更特异性治疗的方法。 面向.虽然人类AML LSC领域具有丰富的研究历史，但许多关键问题仍然有待解决。 被解决。基于细胞表面标志物的表达，能否更严格地鉴定和分离LSC？ LSC的哪些特征或项目与临床结局相关？LSC的负面预测- 相关基因调控LSC功能？非LSC原始细胞是否影响LSC的特性？做AML 亚种群动态影响LSC属性？本提案旨在通过以下途径解决这些问题： 基于LSC表现出不同的功能特性的假设， 有助于AML发病机制、对治疗的反应和临床结果的生物学程序。 因此，这些LSC代表了开发治愈性疗法的关键细胞靶标。

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.