TEL/AML1 FUSION IN PEDIATRIC ALL

描述：(逐字改编自调查人员摘要)TEL/AML1是 儿童急性淋巴细胞白血病最常见的基因重排 (所有)，约占病例的25%。私家侦探和其他人， 报道称，在回顾性研究中，TEL/AML1具有良好的预后。 然而，关于TEL-AML1的预后价值存在争议。二 中心最近报告说，TEL/AML1复发的发生率为 与诊断时相似，表明重排不能提供 预后良好。这种差异可能反映了结果的真正差异。 在这一亚组患者的中心之间，或可能反映了选择 回顾研究中固有的偏见。这项建议的第一个具体目标是 将检验TEL/AML1基因对急性髓细胞白血病预后有利的假设 未来的踪迹。TEL/AML1基因突变的发生率及预后意义 基因重排将被前瞻性地确定在新生的儿童中 都诊断出来了。他们将进一步确定量化最低限度 残留疾病测量可以确定那些TEL/AML1阳性的患者 那些治愈了他们的疾病的人与那些注定要复发的人。这个 第二个特定目标是建立TEL/AML1白血病的小鼠模型。 初步数据表明，仅表达TEL/AML1是不够的 用于体外或体内转化造血细胞。他们将测试 假设人类白血病中存在的额外突变 具有TEL/AML1重排的细胞需要进行转化 通过电话/AML1。已知TEL/AML1基因重排与 随着残留的TEL等位基因的丢失，以及TEL/AML1阳性的子集 患者p16基因缺失。因此，他们将把重点放在将 允许TEL/AML1在TEL和p16缺失的背景中表达。这个 这项提案的两个具体目标是相辅相成的。第一个具体目标 应提供有关卵巢癌预后价值的明确信息 儿童B细胞ALL中TEL/AML1基因重排的研究基于这些数据，它 也许有可能考虑替代治疗ALL的方法。特定的 目标2将重点发展TEL/AML1介导的动物模型 白血病可能被证明在测试和评估替代方案中有用 方法，并定义那些对 造血细胞的转化。

DESCRIPTION: (adapted verbatim from the investigator's abstract) TEL/AML1 is the most common gene rearrangement in pediatric acute lymphoblastic leukemia (ALL), accounting for approximately 25% of cases. The PI and others, have reported that TEL/AML1 confers a favorable prognosis in retrospective studies. However, controversy has arisen regarding the prognostic value of TEL-AML1. Two centers have recently reported that the incidence of TEL/AML1 at relapse is similar to that at diagnosis, suggesting that the rearrangement does not confer a favorable prognosis. The disparity may reflect true differences in outcome between centers for this subgroup of patients, or may reflect the selection bias inherent in retrospective studies. The first specific aim of this proposal will test the hypothesis that TEL/AML1 confers a favorable prognosis in a prospective trail. The incidence and prognostic significance of the TEL/AML1 gene rearrangement will be determined prospectively in children with newly diagnosed ALL. They will further determine whether quantitative minimal residual disease measurements can delineate those TEL/AML1 positive patients that are cured of their disease versus those that are destined to relapse. The second specific aim is to develop a murine model for TEL/AML1 leukemia. Preliminary data indicates that expression of TEL/AML1 alone is not sufficient for transformation of hematopoietic cells in vitro or in vivo. They will test the hypothesis that additional mutations that are present in human leukemic cells with the TEL/AML1 rearrangement are required for transformation mediated by TEL/AML1. It is known that the TEL/AML1 gene rearrangement is associated with loss of the residual TEL allele, and that a subset of TEL/AML1 positive patients are p16 deficient. They will therefore focus on strategies that will allow for expression of TEL/AML1 in both TEL and p16 deficient backgrounds. The two specific aims of this proposal are complementary. The first specific aim should provide definitive information about the prognostic value of the TEL/AML1 gene rearrangement in pediatric B cell ALL. Based on these data, it may be possible to consider alternative approaches to therapy of ALL. Specific aim 2 will focus on the development of an animal model of TEL/AML1-mediated leukemia that may prove useful in testing and evaluating alternative approaches, and defining those genetic events that are critical for the transformation of hematopoietic cells.