Cell Cycle Controlling Genes in Adult Acute Lymphoma

成人急性淋巴瘤的细胞周期控制基因

• 批准号: 6702864
• 负责人: GUILLERMO GARCIA-MANERO
• 金额: $ 13.59万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-06 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6702864
• 关键词: CpG islands; DNA methylation; acute lymphocytic leukemia; adult human (21+); bone marrow transplantation; cancer registry /resource; cancer risk; cell growth regulation; clinical research; data collection methodology /evaluation; gene expression; gene targeting; genetic markers; human subject; long term survivor; molecular pathology; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer relapse /recurrence; neoplastic process; nucleic acid sequence; polymerase chain reaction; prognosis; regulatory gene; statistics /biometry; therapy design /development

DESCRIPTION (provided by applicant): Adult acute lymphocytic leukemia (ALL) consists of a heterogeneous group of lymphoid malignancies. Treatment is stratified based on the presence of the Philadelphia chromosome (Ph), t(9;22) that occurs in 15% to 25% of patients. The rest of patients (Ph negative ALL) are routinely treated with intensive chemotherapy programs that do not discriminate against specific molecular characteristics. Although initial complete remission rates are in excess of 70%, long-term survival may vary from less than 5% for Ph positive to 35% for Ph negative patients. It is therefore of great importance to develop molecular tools to identify patients at high risk for relapse that may benefit from specific therapeutic interventions. Aberrant DNA methylation of promoter associated CpG islands is frequently observed in ALL. Genes involved directly or indirectly in cell cycle control appear to be particularly targeted in this disease, with methylation of p73, p15 or p57KIP2 occurring in 11% to 34% of patients. Preliminary data suggests that methylation of these genes identifies an ALL group at high risk for relapse that cannot otherwise be identified. Here, we propose the hypothesis that methylation of 2 or 3 genes of a pathway including p73, p15 and p57KIP2 identifies a subgroup of patients with ALL with poor prognosis. To test this hypothesis, we propose the following specific aim: to evaluate the methylation status of p73, p15 and p57KIP2 in a cohort of 300 patients with ALL homogeneously treated at our institution, and correlate this with survival. The sample size will provide enough power to allow for multivariate analysis. Analysis of DNA methylation will be performed using bisulfite PCR methods, and will be confirmed using bisulfite sequencing in selected cases. The implications of this project include the identification of a subgroup of patients with poor prognosis that may benefit from targeted therapies using hypomethylating agents and/or early allogeneic bone marrow transplantation in first complete remission.

描述(申请人提供)：成人急性淋巴细胞性白血病(ALL)由一组不同种类的淋巴系恶性肿瘤组成。根据出现在15%到25%的患者中的费城染色体(Ph)，t(9；22)的存在，治疗是分层的。其余患者(Ph阴性ALL)常规接受不歧视特定分子特征的强化化疗方案。虽然初始完全缓解率超过70%，但Ph阳性患者的长期存活率可能不到5%，Ph阴性患者的长期存活率可能不同。因此，开发分子工具来识别可能受益于特定治疗干预的高复发风险患者是非常重要的。启动子相关的CpG岛DNA甲基化异常在ALL中经常被观察到。直接或间接参与细胞周期控制的基因似乎特别针对这种疾病，11%至34%的患者发生p73、p15或p57Kip2的甲基化。初步数据表明，这些基因的甲基化识别出ALL组具有复发的高风险，否则无法识别。在这里，我们提出的假设是，包括p73、p15和p57Kip2在内的一个通路中的2或3个基因甲基化可以识别预后不良的ALL患者亚群。为了验证这一假设，我们提出了以下具体目标：评估在我们机构接受同种治疗的300例ALL患者中p73、p15和p57Kip2的甲基化状态，并将其与生存相关。样本量将提供足够的能量来进行多变量分析。DNA甲基化分析将使用亚硫酸氢盐聚合酶链式反应方法进行，并将在选定的病例中使用亚硫酸氢盐测序进行确认。该项目的意义包括确定一组预后较差的患者，这些患者可能受益于首次完全缓解时使用低甲基化药物的靶向治疗和/或早期异基因骨髓移植。