MOLECULAR CHANGES IN CHROMOSOME 7 IN ACUTE MYELOGENOUS LEUKEMIA

急性髓性白血病 7 号染色体的分子变化

• 批准号: 6338687
• 负责人: Lalitha Nagarajan
• 金额: $ 16.32万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-04 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6338687
• 关键词: acute myelogenous leukemia; artificial chromosomes; biomarker; chromosome deletion; chromosome walking; clinical research; cytogenetics; fluorescent in situ hybridization; gene rearrangement; genetic library; genetic mapping; genotype; human genetic material tag; human subject; human therapy evaluation; human tissue; leukopoiesis; loss of heterozygosity; molecular cloning; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; northern blottings; polymerase chain reaction; prognosis

Acute myelogenous leukemia (AML) cells represent a state of impaired differentiation, enhanced growth and survival of the myeloid progenitors. The tight correlation between cytogenetic alterations and response to therapy is indicative of a cause and effect relationship between the genotype and the disease phenotype. Acquired partial or complete deletion of the long arm of chromosome 7 (7q- or -7) seen in 22% of AML cases, constitutes the most common Cytogenetic anomaly and is associated with poor prognosis. The limits of the interstitial 7q deletions may vary from patient to patient, however there are critical regions of overlap that are consistently deleted. We hypothesize an important role for conversion to hemizygosity at these loci in the evolution of the abnormal phenotype. The studies described here are aimed at understanding the biology and clinical course of the disease in patients with poor prognosis. Our investigations will aim at: l) Molecular delineation of the critical regions of loss in chromosome 7 by loss of heterozygosity analyses; 2) Isolation of genomic clones for the critical loci from a normal human genomic library in Yeast Artificial Chromosome vector; 3) Long range restriction map of the clones isolated in #2 and search for rearrangements of the critical loci in poor prognosis patients; 4) a) Determination of the stage of myeloid maturation at which the anomalies of chromosomes 5 and 7 occur; and b) Comparison of growth factor and chemotherapy response in vitro and in vivo of patients with poor prognosis. A correlation will be made between the genotype of chromosomes 5 and 7 loci and the response to therapy. These studies will provide clues on the molecular mechanisms underlying the refractoriness seen in patients with abnormalities of chromosome 5 and 7.

急性骨髓性白血病（AML）细胞代表 分化受损，增长和生存 髓样祖细胞。细胞遗传学之间的紧密相关性 改变和对治疗的反应表明了原因和 基因型与疾病之间的效果关系 表型。获得长臂的部分或完全删除 在22％的AML病例中，构成22％的染色体7（7q-或-7） 最常见的细胞遗传异常，与较差有关 预后。间隙7Q删除的限制可能会有所不同 从患者到患者，但是有关键的区域 始终删除的重叠。我们假设一个重要的 在这些基因座的进化中转化为半合子的作用 异常表型。此处描述的研究针对 了解该疾病的生物学和临床过程 预后不良的患者。我们的调查将针对：l） 关键损失区域的分子描述 通过杂合性分析的丧失染色体7染色体； 2）隔离 正常人基因组的关键基因座的基因组克隆 酵母人工染色体载体中的图书馆； 3）远距离 ＃2中隔离的克隆的限制图并搜索 不良预后患者关键基因座的重排； 4） a）确定骨髓成熟的阶段 发生染色体5和7的异常； b）比较 生长因子和化学疗法反应在体外和体内 预后不良的患者。将在 染色体5和7基因座的基因型以及对 治疗。这些研究将为分子提供线索 患者患者的磨难性机制 5和7染色体的异常。