Leukemia Stem Cell Properties and Relevance During Therapy for AML

描述(由申请人提供)：急性髓系白血病的干细胞模型提出白血病干细胞群体LSC负责维持疾病。将LSCs与其正常对应细胞区分开来的特性已被提出，并可能成为这种致命疾病的新疗法的靶点。除了有研究表明复发风险与患者缓解期骨髓中CD45+CD34+CD38低细胞的频率有关外，几乎没有证据表明该模型具有临床意义。我们研究的目标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。从确诊和复发时接受急性髓细胞白血病治疗的患者分离并从功能上验证LSC群体。)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。以确定先前报告的LSC特定属性是否保持在缓解状态。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。我们已经鉴定了正常和白血病CD45+CD34+CD38low细胞的表面抗原表达，并鉴定了差异表达的表面标志，允许在缓解状态下分离白血病人群。我们将分析治疗前和复发后样本中的候选人群，并进行NOD/SCID植入分析，以确定患者特有的LSCs。然后，我们将分离和鉴定LSC群体中信号调节失调和NFKB激活的情况。然后，我们将利用患者特有的LSC表面抗原图谱从患者的缓解样本中分离LSC，并确认或驳斥我们的假设，即LSC的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。 公共卫生相关性：恶性肿瘤的癌症干细胞模型提出，一小群癌细胞启动和维持肿瘤，代表了复发的治疗难治性资源。这项多中心的努力代表了评估患者间变异性程度和个体患者癌症干细胞在治疗期间的表型稳定性的第一次前瞻性努力。拟议研究的结果将是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/相关性方面迈出的强有力的第一步。

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.