Clinical Significance of Residual Myeloid Leukemia

残留粒细胞白血病的临床意义

• 批准号: 7094028
• 负责人: DARIO CAMPANA
• 金额: $ 25.85万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7094028
• 关键词: blood; bone marrow; children; clinical research; leukemia; stem cells

DESCRIPTION (provided by applicant): Approximately half of children with acute myeloid leukemia (AML) eventually succumb to their disease. The long-term objective of the proposed research is to improve the clinical management of these patients (and hence their outcome) through sensitive identification of minimal residual disease (MRD) and tracking of leukemia stem cells. A flow cytometric method developed in the applicant's laboratory can distinguish 1 leukemic myeloid cell among 1000 or more normal hematopoietic cells and, in preliminary studies, was successfully applied in monitoring MRD in 85% of children with AML. A positive MRD finding after remission induction was the most powerful predictor of treatment failure.The studies proposed in this application are grounded in a multi-institutional study of AML, which specifies sequential MRD examinations in bone marrow and peripheral blood in approximately 200 children with newly diagnosed AML. Aim 1 is to extend sensitive MRD monitoring (i.e., 1 AML cell in 10,000 or more normal cells) to all children with AML by identifying novel leukemic cell markers. The proposed strategy relies on comparison of the gene expression profiles of AML cells (150 cases already studied) with those of normal immature myeloid counterparts to identify genes differentially expressed in AML. MRD detection by the newly identified markers will be tested against standard flow cytometric and molecular MRD assays. There is mounting evidence that AML is driven by a distinct subset of transformed hematopoietic stem cells, which are likely to be the most relevant targets for effective AML therapy. However, the clinical significance of leukemia stem cells in AML has not yet been systematically addressed. Thus, studies in Aim 2 will rely on newly-developed flow cytometric methods and on leukemia cell growth assays in vitro and in vivo to establish the prevalence of AML stem cells at diagnosis and determine the prognostic impact of their persistence. Aim 3 seeks to assess the clinical utility of MRD assay applied to peripheral blood instead of bone marrow. Based on preliminary results, the expectation is that improvements in the sensitivity of MRD assays will allow MRD to be identified in the peripheral blood of most if not all patients with bone marrow MRD, enhancing the prospects for more frequent MRD monitoring in children with AML. Studies in this aim will determine whether higher levels of blood MRD and of circulating leukemic stem cells correlate with a higher risk of relapse.

描述（由申请人提供）：大约一半患有急性髓系白血病 (AML) 的儿童最终死于该病。拟议研究的长期目标是通过灵敏地识别微小残留病（MRD）和追踪白血病干细胞来改善这些患者的临床管理（从而改善他们的结果）。申请人实验室开发的流式细胞术方法可以从1000个或更多正常造血细胞中区分出1个白血病骨髓细胞，并在初步研究中成功应用于监测85%的AML儿童的MRD。缓解诱导后的阳性 MRD 发现是治疗失败的最有力预测因素。本申请中提出的研究以 AML 的多机构研究为基础，该研究规定对大约 200 名新诊断的 AML 儿童进行骨髓和外周血的连续 MRD 检查。目标 1 是通过识别新的白血病细胞标志物，将敏感的 MRD 监测（即 10,000 个或更多正常细胞中的 1 个 AML 细胞）扩展到所有 AML 儿童。所提出的策略依赖于 AML 细胞（已研究 150 个病例）的基因表达谱与正常未成熟骨髓细胞的基因表达谱的比较，以识别 AML 中差异表达的基因。新鉴定的标记物的 MRD 检测将根据标准流式细胞术和分子 MRD 测定进行测试。越来越多的证据表明，AML 是由转化造血干细胞的一个独特子集驱动的，这些细胞可能是有效 AML 治疗的最相关靶点。然而，白血病干细胞在 AML 中的临床意义尚未得到系统解决。因此，目标 2 的研究将依赖于新开发的流式细胞术方法以及体外和体内白血病细胞生长测定，以确定诊断时 AML 干细胞的患病率，并确定其持续存在的预后影响。目标 3 旨在评估应用于外周血而不是骨髓的 MRD 测定的临床效用。根据初步结果，预计 MRD 检测灵敏度的提高将能够在大多数（如果不是全部）骨髓 MRD 患者的外周血中识别出 MRD，从而增强对 AML 儿童进行更频繁的 MRD 监测的前景。这一目标的研究将确定较高水平的血液 MRD 和循环白血病干细胞是否与较高的复发风险相关。