IMMUNOGLOBULIN GENE ARRANGEMENT EXPRESSION IN LEUKEMIA

白血病中免疫球蛋白基因排列的表达

• 批准号: 6172452
• 负责人: Geoffrey A. Neale
• 金额: $ 24.03万
• 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 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6172452
• 关键词: acute lymphocytic leukemia; bone marrow exam; cancer risk; clinical research; gene induction /repression; gene mutation; gene rearrangement; human subject; immunoglobulins; minimal residual disease; neoplasm /cancer genetics; nucleic acid sequence; polymerase chain reaction; racial /ethnic difference

DESCRIPTION: (adapted from the investigator's abstract) The overall goal of the proposed research is to determine the potential clinical utility of the analysis of minimal residual disease in patients with leukemia, and to understand the dynamics of the leukemic cell population during and following treatment. The leukemic clone is identified by the unique sequence of nucleotides present at the junction(s) of the variable, diversity, and joining regions of the immunoglobulin (lg) and T cell receptor (TCR) genes. Amplification of rearrangements by the polymerase chain reaction (PCR) followed by hybridization with an oligonucleotide probe containing the junctional sequences from the leukemic cell lg or Tcr gene allows the investigators to determine whether the cells from the leukemic clone are present, and the approximate percentage of the total that they represent. The rearranged genes from the patients with B precursor cell acute lymphoblastic leukemia (ALL) show a higher than expected rate of base pair changes from the germline sequence, indicating that perhaps somatic mutation is occurring prior to surface display of lg. To determine whether PCR analysis of gene rearrangements is useful in tracking residual disease and whether somatic mutation occurs in early B progenitor cells the following specific aims are proposed: 1) Test the hypothesis that the kinetics of disappearance of the leukemic clone during the first three months of therapy can be used prognostically to determine risk groups. Bone marrow samples taken during the first three months following diagnosis from patients being treated with various chemotherapeutic regimens will be analyzed for the extent of residual disease of PCR. Included will be patients with high and low risk features, and patients of different racial backgrounds, to determine if there are race-based differences in drug sensitivity. 2) Test the hypothesis that analysis of residual disease levels during maintenance therapy can identify impending relapse. Preliminary data indicate that PCR analysis of bone marrow samples can identify impending relapse, but no large-scale prospective study has been performed. Bone marrow samples will be analyzed at three month intervals for residual disease and determine if relapse can accurately be predicted. 3) Continue to examine the possibility that somatic mutation is occurring in pre-B and early B progenitor cell acute lymphoblastic leukemia. 4) Develop methods to automate quantitation of residual leukemia. Successful completion of the specific aims are expected to provide considerable new insight into the dynamics of the leukemic cell population during therapy, and will determine whether PCR determination of residual disease is a clinically useful tool upon which future clinical trials can be based.

描述：（改编自研究者摘要） 拟议的研究是为了确定潜在的临床效用， 白血病患者微小残留病的分析， 了解白血病细胞群体的动态过程中和以下 治疗 白血病克隆是由独特的序列， 存在于可变的、多样性的和 连接免疫球蛋白（lg）和T细胞受体（TCR）基因的区域。 通过聚合酶链反应（PCR）扩增重排 然后与含有寡核苷酸探针的寡核苷酸探针杂交， 来自白血病细胞Ig或Tcr基因的连接序列允许 研究人员确定来自白血病克隆的细胞是否 目前，以及他们所代表的总数的近似百分比。 B前体细胞急性白血病患者基因重排的研究 淋巴细胞白血病（ALL）显示出比预期更高的碱基对比率， 从种系序列的变化，表明也许体细胞突变， 在Ig表面展示之前发生。为了确定PCR是否 基因重排分析可用于追踪残留疾病， 体细胞突变是否发生在早期B祖细胞中， 具体目标是：1）测试的假设，动力学的 在治疗的头三个月白血病克隆的消失 可用于诊断风险人群。 骨髓样品 在诊断后的前三个月内， 将分析用各种化疗方案治疗的患者的 PCR残留病的程度。 将纳入高血压患者， 低风险特征和不同种族背景的患者， 确定药物敏感性是否存在种族差异。 2)测试 假设分析维持期间的残留疾病水平 治疗可以识别即将复发。 初步数据显示，PCR 骨髓样本的分析可以识别即将复发，但没有 进行了大规模前瞻性研究。 骨髓样本将 每隔三个月分析一次残留疾病， 可以准确预测复发。 3)继续调查 体细胞突变发生在前B和早期B祖细胞中 急性淋巴母细胞白血病 4)开发自动定量方法 白血病残留 具体目标的顺利完成是 预计将提供相当多的新的洞察力的动态 白血病细胞群体在治疗过程中，并将确定是否PCR 确定残留疾病是临床上有用的工具， 未来的临床试验可以根据。