IMMUNOGLOBULIN GENE ARRANGEMENT/EXPRESSION IN LEUKEMIA

白血病中的免疫球蛋白基因排列/表达

• 批准号: 2094673
• 负责人: GEOFFREY R KITCHINGMAN
• 金额: $ 19.77万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-07-01 至 1996-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2094673
• 关键词: DNA footprinting; T lymphocyte; acute lymphocytic leukemia; acute myelogenous leukemia; clone cells; early diagnosis; gene expression; gene rearrangement; human subject; immunoglobulins; neoplasm /cancer diagnosis; neoplasm /cancer remission /regression; neoplastic cell; nucleic acid sequence; polymerase chain reaction

DESCRIPTION (Adapted from Applicant's Abstract): Despite improvements in treatment modalities, approximately one-third of children with acute lymphoblastic leukemia (ALL), and two-thirds of patients with acute myeloid leukemia (AML) are not presently being cured. Following hematologic relapse, 80% of the patients expire within 6 months. At diagnosis, patients have a tumor burden of approximately one billion leukemic cells, and at the present time it is not known how effective cytoreductive therapy is. This is because residual leukemic blasts representing <5% of the bone marrow cell population may remain unseen by conventional morphological examination, and other methods of detection of residual leukemic cells are either insufficiently sensitive to significantly improve on this detection level, or require considerable technical expertise and can only be applied to small numbers of samples. It is possible that early detection of minimal residual disease (MRD) when the leukemic burden is low would allow intervention with alternative treatment strategies that may improve the patient's possibility of survival. The polymerase chain reaction (PCR) represents a technique that is potentially applicable to this problem. The sensitivity of the technique is sufficient to detect one cell in 100,000, and if specificity for the leukemic clone can be achieved then use of this technique will significantly improve our ability to detect occult leukemic cells. Leukemic clone specificity can be achieved through the use of immunoglobulin and T cell receptor gene rearrangements which can be found in almost 100% of B and T lineage ALLs, and in about 20% of AMLs. The dynamics of the leukemic cell population during remission will therefore be investigated utilizing the PCR to detect minimal residual disease. They will attempt to determine if detectable residual leukemic cells are a harbinger of impending relapse. Methods will be developed to make the PCR technique generally applicable to leukemias with gene rearrangements by identifying primers from immunoglobulin and T cell receptor genes that can be used for this purpose. With such primers, they will examine serial DNA samples from a large number of patients, some of whom remain in continuous remission and some of whom have relapsed. Patients undergoing autologous and allogeneic bone marrow transplantation will be examined before and after infusion of marrow. Overall, these studies should shed considerable light on the dynamics of the leukemic cell population during clinical remission, and determine whether the PCR can be used to predict impending relapse. A positive outcome of these experiments may allow future modifications in therapeutic modalities that are geared toward the actual level of leukemic cells in the body.

描述(改编自申请者摘要)：尽管在 治疗方式，大约三分之一的急性胰腺炎儿童 淋巴细胞白血病(ALL)和三分之二的急性髓系患者 白血病(AML)目前还没有治愈。遵循血液学 复发，80%的患者在6个月内死亡。在诊断时， 患者的肿瘤负担约为10亿个白血病细胞， 目前尚不清楚细胞减数疗法有多有效。 是。这是因为残留的白血病母细胞占骨骼的5%。 骨髓细胞群可能仍未被常规形态观察到 检测残留白血病细胞的其他方法有 要么不够灵敏，不能显著改善这种检测 级别，或者需要大量的技术专长，并且只能应用 到少量的样品。有可能及早发现 白血病负担低时的微小残留病(MRD)将允许 采用替代治疗策略进行干预，可能会改善 病人存活的可能性。 聚合酶链式反应(PCR)代表了一种 可能适用于这个问题。这项技术的敏感性 足以检测出100,000个细胞中的一个，如果对 可以实现白血病克隆，那么使用这项技术将 显著提高了我们检测隐匿性白血病细胞的能力。 白血病克隆特异性可以通过使用 免疫球蛋白与T细胞受体基因重排 在几乎100%的B和T系ALL中，以及大约20%的AML中。 缓解期间白血病细胞种群的动态将 因此利用聚合酶链式反应来检测最小残留 疾病。他们将尝试确定是否可以检测到残留的白血病 细胞是即将复发的先兆。方法将被开发为 使聚合酶链式反应技术普遍适用于基因白血病 从免疫球蛋白和T细胞中鉴定引物的重排 可用于此目的的受体基因。有了这样的底漆，他们 将检查大量患者的连续DNA样本，其中一些 他们仍然处于持续缓解状态，其中一些人已经复发。 接受自体和异基因骨髓移植的患者 将在输注骨髓前后进行检查。 总体而言，这些研究应该会对 临床缓解期的白血病细胞群，并确定 聚合酶链式反应能否用来预测即将到来的复发。积极的一面 这些实验的结果可能会允许未来对治疗方法进行修改 适合于白血病细胞的实际水平的模式 尸体。