Clinical Significance of Residual Myeloid Leukemia

残留粒细胞白血病的临床意义

• 批准号: 7423894
• 负责人: DARIO CAMPANA
• 金额: $ 26.02万
• 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 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7423894
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Acute leukemia; Address; Adult Acute Myeloblastic Leukemia; Biological Assay; Blood; Blood specimen; Bone Marrow; Cells; Characteristics; Child; Childhood; Clinical; Clinical Management; Correlative Study; Databases; Detection of Minimal Residual Disease; Diagnosis; Disease; Disease Marker; Flow Cytometry; Gene Expression; Genes; Hematopoietic; Hematopoietic stem cells; Immunophenotyping; Institution; Laboratories; Leukemic Cell; Marrow; Measurement; Methods; Molecular; Molecular Profiling; Monitor; Myelogenous; Myeloid Cells; Myeloid Leukemia; Newly Diagnosed; Normal Cell; Outcome; Patients; Population; Prevalence; Prevention; Relapse; Remission Induction; Research; Residual Neoplasm; Residual Tumors; Residual state; Risk; Sampling; Specific qualifier value; Specimen; Standards of Weights and Measures; Stem cells; Testing; Time; Treatment Failure; Treatment outcome; base; cell growth; clinically significant; expectation; follow-up; improved; in vitro Assay; in vivo; insight; leukemia; leukemic stem cell; novel; peripheral blood; prognostic; reconstitution; response; treatment trial

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)：大约一半的急性髓系白血病(AML)儿童最终死于他们的疾病。拟议研究的长期目标是通过敏感地识别微小残留病(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)。本实验室建立的流式细胞术可将1000个或更多的正常造血细胞中的1个白血病髓系细胞区分开来，并在初步研究中成功地应用于85%的AML儿童的MRD监测。在缓解诱导后发现MRD阳性是治疗失败的最有力的预测因素。这项申请中提出的研究基于一项关于AML的多机构研究，该研究指定了大约200名新诊断的AML儿童的骨髓和外周血中的连续MRD检查。目标1是通过识别新的白血病细胞标记物，将敏感的MRD监测(即，在10,000个或更多正常细胞中有1个AML细胞)扩展到所有AML儿童。该策略依赖于比较AML细胞(已有150例)和正常未成熟髓系细胞的基因表达谱，以确定在AML中差异表达的基因。用新确定的标记检测MRD将与标准的流式细胞仪和分子MRD分析进行比较。越来越多的证据表明，急性髓细胞白血病是由转化的造血干细胞亚群驱动的，这些干细胞可能是有效治疗急性髓细胞白血病最相关的靶点。然而，白血病干细胞在急性髓细胞白血病中的临床意义尚未得到系统的阐述。因此，AIM 2的研究将依赖于新开发的流式细胞术方法和体外和体内白血病细胞生长分析，以确定AML干细胞在确诊时的患病率，并确定它们持续存在的预后影响。目的3评价MRD检测代替骨髓应用于外周血的临床应用价值。根据初步结果，预计MRD检测灵敏度的提高将使大多数(如果不是全部)骨髓MRD患者的外周血液中都能发现MRD，从而增加对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血液MRD和循环白血病干细胞水平较高是否与复发风险较高相关。