Etiology of Treatment Induced Secondary Leukemia

描述（由申请人提供）：治疗相关骨髓增生异常综合征（t-MDS）或急性髓性白血病（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。 已经认识到t-MDS/t-AML的几个临床和生物学子集，其与针对原发疾病接受的治疗相关。 最常见的类型在接受烷化剂的患者中潜伏期约5年后出现，其特征在于5号和/或7号染色体的丢失或缺失。 相比之下，使用靶向拓扑异构酶II的药物治疗后发生t-AML的患者通常在11 q23处复发MLL基因易位，或在21 q22处复发RUNX 1/AML 1基因易位。 该项目的目标是阐明导致t-MDS/t-AML的分子机制。 我们提出了四个综合项目，集中在恶性转化中染色体异常的作用。 罗利和Zeleznik-Le博士致力于分析涉及MLL和RUNX 1的重复易位。 罗利博士将分别专注于MLL和RUNX 1及其伴侣基因AF 9和CBP以及ETO和MDS 1的结构分析。 这些研究的总体目标是确定MLL，RUNX 1及其伴侣基因中的结构元件，这些结构元件可能参与介导染色体易位。 Zeleznik-Le博士将研究MLL融合蛋白介导恶性转化的机制。 她将专注于参与t-MDS的MLL-CBP融合基因。 Le Beau博士将专注于在5 q上鉴定髓性白血病肿瘤抑制基因。 在补充研究中，Shannon博士将专注于7 q上候选肿瘤抑制基因的鉴定和功能分析。 此外，两位研究者还将评价除肿瘤抑制基因以外的其他机制在5号或7号染色体异常的t-MDS/t-AML发病机制中的作用。 这些项目利用患者访问、数据管理和细胞存储核心。 核心确保白血病标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。 该计划项目通过使用一组常见的患者进行分子分析来整合，目的是提高对t-AML病因学的理解。

DESCRIPTION (provided by applicant): Therapy-related myelodysplastic syndrome (t-MDS) or acute myeloid leukemia (t-AML) is late complications of the successful use of cytotoxic therapy for the treatment of malignant diseases. Several clinical and biological subsets of t-MDS/t-AML have been recognized, which correlate with the therapy received for the primary disease. The most common type presents after a latency of about 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 of the MLL gene at 11q23, or the RUNX1/AML1 gene at 21q22. The goal of this program project is to elucidate the molecular mechanisms leading to t-MDS/t-AML. We propose four integrated projects that focus on the role of chromosomal abnormalities in malignant transformation. Drs. Rowley and Zeleznik-Le are devoting their efforts to the analysis of recurring translocations involving MLL and RUNX1. Dr. Rowley will focus on a structural analysis of MLL and RUNX1 and their partner genes, AF9 and CBP, and ETO and MDS1, respectively. The overall goal of these studies is to identify structural elements within MLL, RUNX1, and their partner genes, which could be involved in mediating chromosomal translocations. Dr. Zeleznik-Le will examine the mechanisms by which MLL-fusion proteins mediate malignant transformation. She will focus on the MLL-CBP fusion gene involved in t-MDS. Dr. Le Beau will focuses on the identification of a myeloid leukemia tumor suppressor gene on 5q. In complementary studies, Dr. Shannon will focuses on the identification and functional analysis of candidate tumor suppressor genes on 7q. In addition, both investigators will evaluate alternative mechanisms other than tumor suppressor genes, in the pathogenesis of t-MDS/t-AML with abnormalities of chromosomes 5 or 7. The projects utilize a Patient Access, Data Management and Cell Storage Core. The Core insures an orderly flow of leukemia specimens to the four projects, and the collection, and analysis of critical clinical, biological, and statistical data. 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-AML.