Etiology of Treatment Induced Secondary Leukemia

描述(申请人提供)：治疗相关骨髓增生异常综合征(t-MDS)或急性髓系白血病(t-AML)是成功使用细胞毒疗法治疗恶性肿瘤的晚期并发症。已经认识到t-MDS/t-AML的几个临床和生物学亚群，它们与接受的原发病治疗相关。在接受烷化剂治疗的患者中，最常见的类型出现在潜伏期约5年后，特征是5号和/或7号染色体的丢失或缺失。相比之下，使用针对拓扑异构酶II的药物治疗后发展为t-AML的患者通常有11q23的MLL基因或21q22的RUNX1/AML1基因的反复易位。本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，重点关注染色体异常在恶性转化中的作用。Rowley博士和Zeleznik-Le博士致力于分析涉及MLL和RUNX1的复发性易位。罗利博士将专注于MLL和RUNX1及其配对基因AF9和CBP，以及ETO和MDS1的结构分析。这些研究的总体目标是确定MLL、RUNX1及其伙伴基因中可能参与介导染色体易位的结构元件。Zeleznik-Le博士将研究MLL融合蛋白介导恶性转化的机制。她将重点研究与t-MDS有关的MLL-CBP融合基因。Le Beau博士将专注于5q上一个髓系白血病肿瘤抑制基因的鉴定。在补充性研究中，香农博士将专注于7q候选抑癌基因的鉴定和功能分析。此外，两位研究人员都将评估在t-MDS/t-AML伴有5号或7号染色体异常的发病机制中，除肿瘤抑制基因外的其他机制。该项目利用了患者访问、数据管理和细胞存储核心。该中心确保白血病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。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，目的是发展对t-AML病因的更好理解。

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.