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表明，白血病干细胞群（LSC）负责维持该疾病。LSCs区别于正常细胞的特性已经被提出，并且可能代表这种致命疾病的新疗法的靶点。除了研究表明复发风险与患者缓解期骨髓中白血病CD45+CD34+CD38low细胞的频率相关外，几乎没有证据表明该模型具有临床相关性。我们研究的目的是明确地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治疗的患者中分离并功能性验证LSC群体；2.)通过直接比较治疗前和复发LSC的表面抗原和分子信号谱来证明LSC表型的稳定性；3.)确定先前报道的LSC特异性是否维持在缓解状态。为了实现这一目标，我们正在将患者聚集到多中心的努力中。我们表征了正常和白血病CD45+CD34+CD38low细胞的表面抗原表达，并鉴定了在缓解状态下允许分离白血病群体的差异表达的表面标记。我们将分析治疗前和复发后样本的候选人群，并进行NOD/SCID植入试验以识别患者特异性LSCs。然后，我们将分离和表征LSC群体的信号失调和NFKB的激活。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LSC，并证实或反驳我们的假设，即LSC特异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LSCs的临床相关性和靶向它们的潜力提供直接证据。