Leukemia Stem Cell Properties and Relevance During Therapy for AML

白血病干细胞特性及 AML 治疗期间的相关性

• 批准号: 7990273
• 负责人: MICHAEL W BECKER
• 金额: $ 16.64万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990273
• 关键词: Accounting; Acute Myelocytic Leukemia; Address; Aspirate substance; Biological; Biological Assay; Bone Marrow; Cell model; Cells; Clinical; Clinical Data; Clinical Research; Complex; Consolidation Therapy; Data; Diagnosis; Disease; Disease Progression; Disease remission; Engraftment; Experimental Models; Frequencies; Goals; Individual; Leukemic Cell; Malignant Neoplasms; Marrow; Modeling; Molecular; NF-kappa B; Outcome; Pathway interactions; Patients; Phenotype; Population; Property; Publications; Recurrent disease; Refractory; Relapse; Reporting; Research; Residual Neoplasm; Resistance; Risk; Sampling; Signal Transduction; Staging; Stem cells; Surface; Surface Antigens; Testing; Time; Work; anticancer research; base; burden of illness; cancer cell; cancer stem cell; chemotherapy; clinical remission; clinically relevant; cohort; experience; improved; leukemia; leukemic stem cell; novel; novel therapeutics; patient population; pre-clinical; programs; prospective; public health relevance; stem cell population; tumor

DESCRIPTION (provided by applicant): The stem cell model for Acute Myelogenous Leukemia proposes that a leukemia stem cell population, LSC, is responsible for maintaining the disease. Properties that distinguish LSCs from their normal counterparts have been proposed and may represent targets for novel therapies for this deadly disease. There is little evidence that the model is clinically relevant apart from studies that demonstrated that the risk of relapse is related to the frequency of leukemic CD45+CD34+CD38low cells in a patient remission marrow. The goal of our research is to unambiguously demonstrate the clinical relevance of the leukemic stem cell model. As a step towards achieving this goal, we propose to 1.) isolate and functionally validate the LSC populations from patients undergoing treatment for AML at time of diagnosis and relapse 2.) to demonstrate the stability of the LSC phenotype by directly comparing the surface antigen and molecular signaling profiles of pre-therapy and relapse LSCs and, 3.) to determine if previously reported LSC specific properties are maintained in the remission state. We are accruing patients to a multi-center effort to accomplish this goal. We have characterized the surface antigen expression of normal and leukemic CD45+CD34+CD38low cells and identified differentially expressed surface markers that allow the isolation of leukemic population during the remission state. We will analyze candidate populations from pre-therapy and post-relapse samples and perform NOD/SCID engraftment assays to identify patient specific LSCs. We will then isolate and characterize the LSC populations with regard to dysregulation of signaling and activation of NFKB. We will then utilize the patient specific LSC surface antigen profile to isolate LSCs from the patients' remission samples and confirm or refute our hypothesis that LSC specific properties are stable throughout the clinical course. Data obtained from this study will provide direct evidence of the clinical relevance of LSCs and the potential of targeting them. PUBLIC HEALTH RELEVANCE: The cancer stem cell model for malignancy proposes that a small population of cancer cells initiate and maintain tumors and represent a therapy refractory resevoir for relapse. This multi-center effort represents the first prospective effort to assess the degree of inter-patient variability and phenotypic stability of an individual patient's cancer stem cells during therapy. The results from the proposed studies will represent a strong first step in verifying the importance/relevance of targeting cancer stem cells in improving outcome for patients with cancer.

描述（由申请人提供）：急性髓性白血病的干细胞模型提出白血病干细胞群LSC负责维持该疾病。人们已经提出了将 LSC 与其正常对应物区分开来的特性，并且可能代表这种致命疾病的新疗法的目标。除了证明复发风险与患者缓解骨髓中白血病 CD45+CD34+CD38low 细胞频率相关的研究外，几乎没有证据表明该模型具有临床相关性。我们研究的目标是明确证明白血病干细胞模型的临床相关性。作为实现这一目标的一步，我们建议 1.) 在诊断和复发时从接受 AML 治疗的患者中分离出 LSC 群体并进行功能验证 2.) 通过直接比较表面抗原来证明 LSC 表型的稳定性以及治疗前和复发 LSC 的分子信号传导谱，3.) 确定先前报道的 LSC 特异性特性是否保持在缓解状态。我们正在招募患者进行多中心努力以实现这一目标。我们表征了正常和白血病 CD45+CD34+CD38low 细胞的表面抗原表达，并鉴定了差异表达的表面标记，这些标记允许在缓解状态下分离白血病群体。我们将分析来自治疗前和复发后样本的候选群体，并进行 NOD/SCID 植入测定，以确定患者特异性 LSC。然后，我们将分离和表征 LSC 群体的信号失调和 NFKB 激活。然后，我们将利用患者特异性 LSC 表面抗原谱从患者缓解样本中分离出 LSC，并证实或反驳我们的假设，即 LSC 特异性特性在整个临床过程中是稳定的。从这项研究中获得的数据将为 LSC 的临床相关性及其靶向潜力提供直接证据。 公共健康相关性：恶性肿瘤的癌症干细胞模型提出，一小群癌细胞会引发并维持肿瘤，并代表治疗难治性复发的水库。这项多中心工作代表了第一个评估治疗期间个体患者癌症干细胞的患者间变异程度和表型稳定性的前瞻性工作。拟议研究的结果将代表在验证靶向癌症干细胞在改善癌症患者预后方面的重要性/相关性方面迈出了强有力的第一步。