ETIOLOGY OF TREATMENT-INDUCED SECONDARY LEUKEMIA

我们建议继续和扩大我们对治疗病因的研究- 相关性急性非淋巴细胞白血病(t-ANLL)。其他支持是 要求继续进行两个项目和一个新项目。我们发现， 正在接受霍奇金病、S病(HD)和非霍奇金病治疗的个人 淋巴瘤(NHL)和t-ANLL患者具有低烷基鸟嘌呤 甲基转移酶(AGT)活性与健康对照或 患有新发ANLL的个人。我们建议检验Low的假设 AGT活性与t-ANLL的发生有关。我们将测试AGT 接受HD放射治疗患者的血药浓度作为对照和意愿 跟踪接受大剂量化疗的患者的AGT活性 BCNU.我们计划开发一种针对AGT的抗体来研究AGT的异质性 淋巴细胞中的这种蛋白质。使用两种方法的可变性研究 染色体基因和基于EB病毒(EBV)的质粒将被 在一系列不同AGT的等基因淋巴母细胞系中进行 内容来确定活性和可变性之间的关系 应用MNNG和BCNU治疗。细胞学测量的染色体断裂 生化将与AGT活性相关联，以测试 假设低水平的AGT会导致较高的突变性。在一个新的 计划中，我们建议识别和分离位于 5号染色体，其功能因隐性突变而改变。 (例如，染色体缺失、点突变和亚显微缺失 在第一个项目中研究的类型)在发病机制中起作用 是ANLL的。为了实现这一目标，调查人员将开发一种体检 5q关键区基因与匿名序列的连锁图谱； 这一图谱将用于检测从白血病细胞中提取的DNA 存在5q缺失的患者，以确定亚显微缺失 或“正常”5号染色体同源物中的其他DNA重排 确定纯合失活的候选基因。这些研究 加入该方案的持续工作将提供更明确的 对t-ANLL病因的认识。

We propose to continue and expand our studies on the etiology of treatment- related acute nonlymphocytic leukemia (t-ANLL). Additional support is requested for two continuing and one new project. We have found that individuals being treated for Hodgkin;s disease (HD) and non-Hodgkin's lymphoma (NHL) as well as individuals with t-ANLL have low alkylguanine methyltransferase (AGT) activity as compared with healthy controls or individuals with ANLL de novo. We propose to test the hypothesis that low AGT activity is related to the development of t-ANLL. We will test AGT levels in patients undergoing radiation therapy for HD as controls and will follow AGT activity in individuals receiving high-dose chemotherapy with BCNU. We plan to develop an antibody to AGT to study the heterogeneity of this protein in lymphoid cells. Studies on mutability using both a chromosomal gene and an Epstein-Barr virus (EBV)-based plasmid will be carried out in a series of isogenic lymphoblastoid lines of differing AGT content to determine the relationship between activity and mutability after treatment with MNNG and BCNU. Chromosome breakage measured cytologically and biochemically will be correlated with AGT activity to test the hypothesis that low levels of AGT lead to higher mutability. In a new program, we propose to identify and isolate the putative genes located on chromosome 5. whose altered function as a result of recessive mutations (e.g., chromosome deletions, point mutations, and submicroscopic deletions of the type studied in the first programs) plays a role in the pathogenesis of ANLL. To accomplish this aim, the investigators will develop a physical linkage map of genes and anonymous sequences in the critical region of 5q; this map will be used to examine the DNA derived from leukemia cell of patients with deletions of 5q in order to identify submicroscopic deletions or other DNA rearrangements in the "normal" chromosome 5 homologue thereby identifying candidate genes for homozygous inactivation. These studies added to the continuing work of the Program will provide more definitive understanding of the etiology of t-ANLL.