EXPLOITATION OF FREQUENT P16 DELETION IN T-ALL THERAPY

描述：(申请者摘要)这是一种生物相关 有两个主要目标的研究：(I)描述临床相关性 T-ALL中新发现的抑癌基因p16及其相关基因p15； 以及(Ii)评估映射到旁边的基因的频繁缺失 P16和MTAP编码，旨在开发MTAP靶向治疗 为了T-ALL。作为POG肿瘤抑制基因的参考实验室 T-ALL，申请者计划收集T-ALL患者的样本 登记参加POG临床试验，并进行以下操作 假设驱动的研究：假设1：p16/p15基因的改变是 T-ALL在确诊和复发时很常见，缺失的比例更高 比突变更普遍，这种改变可能与 临床结果不佳。我们的方法将是比较 P16/p15在诊断和复发T-ALL样本之间的改变 将结果与患者的临床特征相关联， 对治疗的反应和无事件生存。假设2：MTAP基因 它与p16基因相邻，常在p16缺失时发生共缺失 都是样品。方法将是确定频率 检测MTAP基因缺失情况，并与p16基因状态进行比较。 假设3：缺乏MTAP基因的T-ALL细胞可能表现为增高 对嘌呤合成抑制剂的敏感性和依赖性增加 蛋氨酸。这可能会导致新的和有选择性的发展 T-ALL的治疗针对MTAP缺乏症。方法将是 测定T-ALL细胞对蛋氨酸耗竭的体外敏感性 和嘌呤合成抑制剂，如ddATHF(5，10- 二氮杂四氢叶酸)和丙氨酸，然后将结果关联起来 具有MTAP基因状态。

DESCRIPTION: (Applicant's Abstract) This is a biological correlative study with two major objectives: (i) to delineate the clinical relevance of p16, a novel tumor suppressor gene and its related gene p15, in T-ALL; and (ii) to assess the frequent deletion of the gene which maps next to p16 and encodes for MTAP, with an aim to develop MTAP-targeted therapies for T-ALL. As a POG reference laboratory for tumor suppressor genes in T-ALL, the applicant plans to collect samples from T-ALL patients enrolled into the POG clinical trials, and carry out the following hypothesis-driven studies: Hypothesis 1: Alterations in p16/p15 genes are common in T-ALL at diagnosis and relapse, with deletion being more prevalent than mutations, and such alterations may be associated with poor clinical outcome. The approach will be to compare the frequency of p16/p15 alterations between diagnosis and relapse T-ALL samples and correlate the results with the clinical features of the patients, response to therapy and event free survival. Hypothesis 2: MTAP gene which is located adjacent to p16 gene, is often co-deleted in p16 deleted T-ALL samples. The approach will be to determine the frequency of deletion of the MTAP gene and compare the results with p16 gene status. Hypothesis 3: T-ALL cells which lack MTAP gene may display increased sensitivity to inhibitors of purine synthesis and increased dependence on methionine. This may lead to the development of new and selective therapies for T-ALL targeted at MTAP deficiency. The approach will be to determine the in vitro sensitivity of T-ALL cells to methionine depletion and purine synthesis inhibitors such as ddATHF (5,10- dideazatetrahydrofolate) and alanosine, and then correlate the results with MTAP gene status.