Etiology of Alkylator-Induced Myeloid Leukemia

描述（由申请方提供）：治疗相关骨髓增生异常综合征（t-MDS）和急性髓性白血病（t-AML）是成功使用细胞毒性治疗治疗恶性疾病的晚期并发症。最常见的类型出现在接受烷化剂治疗的患者中，潜伏期约为5年，其特征是5号和/或7号染色体丢失或缺失。相比之下，在用靶向拓扑异构酶II的药物治疗后发展为t-AML的患者通常具有复发性易位，例如，MLL基因位于11 q23。t-MDS/t-AML代表癌症的重要模型，原因有几个。首先，由于癌症幸存者人数的增加，这种疾病的发病率正在上升。第二，t-AML的发展提供了一个独特的机会来研究诱变剂对人类致癌作用的影响，以及遗传易感性和易患癌症的因素。t-AML患者的生存时间通常很短，需要新的治疗方法。 该项目的目标是阐明导致t-MDS/t-AML的分子机制和遗传易感性。Onel博士（项目1）将对t-AML患者的生殖系DNA进行全基因组关联研究，以确定可能是t-AML遗传风险因素或生物标志物的拷贝数改变和遗传变异。在补充研究中，Downing博士（项目2）将进行全基因组研究，通过分析白血病细胞来绘制与t-AML相关的拷贝数变化和体细胞改变，其中许多与项目1，3和4中研究的样本配对。Le Beau博士（项目3）专注于5 q上髓性白血病肿瘤抑制基因（TSG）的鉴定和功能分析。在补充研究中，Shannon博士（项目4）专注于7 q上候选TSG的识别和功能分析。此外，这两个项目都强调与5 q或7 q上的髓系白血病抑制基因合作的继发突变的鉴定。 每个项目都使用患者访问、数据管理和单元存储核心（核心A）以及管理核心（核心B）。核心A确保白血病和生殖细胞样本有序地流向四个项目，并收集和分析关键的临床，生物和统计数据。核心B（行政核心）为该计划提供行政和组织支持。该项目通过使用一组常见的患者进行分子分析来整合，目的是加深对t-MDS/t-AML病因学、t-MDS/t-AML发病机制中涉及的遗传途径以及t-AML遗传易感性的理解。这些研究可能最终导致个体化癌症预防和早期检测策略的发展，例如改变主要治疗。

DESCRIPTION (provided by applicant): Therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) are late complications of the successful use of cytotoxic therapy for the treatment of malignant diseases. The most common type presents after a latency of ~5 years in patients who received alkylating agents, and is characterized by loss or deletion of chromosomes 5 and/or 7. In contrast, patients who develop t-AML following treatment with drugs targeting topoisomerase II typically have recurring translocations, e.g., MLL gene at 11q23. t-MDS/t-AML represents an important model for cancer for several reasons. First, the incidence of this disorder is rising, as a result of the increasing number of cancer survivors. Second, the development of t-AML provides a unique opportunity to examine the effects of mutagens on carcinogenesis in humans, as well as the issue of genetic susceptibility and factors that predispose to the development of cancer. Survival times of t-AML patients are typically short, and new therapeutic approaches are needed. The goal of this program project is to elucidate the molecular mechanisms and genetic susceptibilities leading to t-MDS/t-AML. Dr. Onel (Project 1) will undertake genome-wide association studies of germline DNA from patients with t-AML to identify copy number alterations and genetic variants that may be genetic risk factors or biomarkers for t-AML. In complementary studies, Dr. Downing (Project 2) will undertake genome-wide studies to map copy number changes and somatic alterations associated with t-AML by analyzing leukemia cells, many of which are paired with samples studied in Projects 1, 3, and 4. Dr. Le Beau (Project 3) focuses on the identification and functional analysis of a myeloid leukemia tumor suppressor gene(s) (TSG) on 5q. In complementary studies, Dr. Shannon (Project 4) focuses on the identification and functional analysis of candidate TSGs on 7q. In addition, both projects emphasize the identification of secondary mutations that cooperate with myeloid leukemia suppressor genes on 5q or 7q. Each project utilizes the Patient Access, Data Management and Cell Storage Core (Core A), as well as the Administrative Core (Core B). Core A insures an orderly flow of leukemia and germline samples to the four projects, and the collection, and analysis of critical clinical, biological, and statistical data. Core B (Administrative Core) provides administrative and organizational support to the Program. The Program Project is integrated by its use of a common set of patients for molecular analysis with the goal of developing an improved understanding of the etiology of t-MDS/t-AML, the genetic pathways involved in the pathogenesis of t-MDS/t-AML, and genetic susceptibility to t-AML. These studies may lead, ultimately, to the development of individualized cancer prevention and early detection strategies, such as altered primary therapy.