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: 3197075
• 负责人: GEOFFREY R KITCHINGMAN
• 金额: $ 11.6万
• 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/3197075
• 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（改编自申请人的摘要）： 治疗方式，大约三分之一的儿童急性 淋巴细胞白血病（ALL）和三分之二的急性髓细胞白血病患者 白血病（AML）目前尚未治愈。 血液学检查后 复发，80%的患者在6个月内死亡。 诊断时， 患者具有约十亿个白血病细胞的肿瘤负荷， 目前尚不清楚细胞减灭疗法 是. 这是因为残留的白血病原始细胞占骨的<5%， 骨髓细胞群可能仍然看不到传统的形态学 检查和其他检测残留白血病细胞的方法， 或者灵敏度不足以显著改善这种检测 水平，或需要相当的技术专长，只能适用于 少量的样本。 有可能早期发现 当白血病负荷低时，微小残留病（MRD）将允许 采用替代治疗策略进行干预， 患者生存的可能性。 聚合酶链反应（PCR）代表了一种技术， 可能适用于这个问题。 这项技术的灵敏度 足以检测100，000个细胞中的一个细胞，如果特异性 可以实现白血病克隆，那么使用该技术将 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 免疫球蛋白和T细胞受体基因重排， 在几乎100%的B和T谱系ALL中，以及在约20%的AML中。 缓解期白血病细胞群的动态变化将 因此，应使用PCR进行研究，以检测最小残留量 疾病 他们将试图确定是否有可检测的残留白血病 细胞是即将复发的预兆。 将制定方法， 使PCR技术普遍适用于白血病基因 通过鉴定免疫球蛋白和T细胞的引物进行重排 可以用于此目的的受体基因。 有了这些引物， 将检查来自大量患者的连续DNA样本，其中一些 这些人仍在持续缓解中，其中一些人已经复发。 接受自体和异体骨髓移植的患者 将在骨髓输注前后进行检查。 总的来说，这些研究应该相当清楚的动态， 临床缓解期间的白血病细胞群体，并确定 PCR是否可用于预测即将发生的复发。 积极的 这些实验的结果可能允许未来的治疗修改， 这些模式是针对白血病细胞的实际水平， 身体