Gene Expression Patterns in Acute Lymphoblastic Leukemia

描述（由申请人提供）：急性淋巴细胞白血病（ALL）是一种 在临床结果中表现出异质性的疾病。 其中一些 异质性反映在存在不同的非随机染色体 易位，这与不同的临床结果。 许多 这些染色体易位导致新的融合基因。 我们假设 这些融合基因诱导异常的基因表达模式， 是这些易位促进发育的机制 从而影响预后。 然而，并非所有的 临床结果的异质性可以用易位来解释。 我们 假设ALL其他特异性异质性特征，如 对化疗剂的可变反应，也反映在不同的 基因表达模式。 本提案中描述的项目的总体目标是使用 ALL中大量基因表达水平的测量， 更好地了解ALL的具体特征。 为了使 这样的测量，我们将利用最近开发的高密度cDNA 微阵列技术 该项目的具体目标是：（1）确定不同的模式， 基因 表达 的 是 关联 与 特别 染色体 t r anslocations，（2）鉴定基因表达的不同模式 与化疗敏感性或耐药相关;（3）使用基因 表达测量，以确定重要的诊断和预后 ALL亚型，以前未被识别，和（4）发展 ALL相关基因转录途径的可测试模型。 通过这项工作，我们期望作出一些重要贡献， 所有人的理解。 首先，我们将更深入地了解 负责ALL发展的分子机制。 二是 深入了解ALL中化疗耐药的机制，因此， 促进开发克服这种阻力的方法。 第三、 通过识别以前未被识别的ALL亚型，我们 期望促进新的、临床上有用的标记物的开发， 指导治疗这种疾病。 第四，通过开发新颖的造型， 技术，我们期望获得更深入的了解基因转录 这些网络在所有人中都很重要。

DESCRIPTION (provided by applicant): Acute lymphoblastic leukemia (ALL) is a disease that exhibits heterogeneity in clinical outcome. Some of this heterogeneity is reflected by the presence of distinct nonrandom chromosomal translocations, which are associated with distinct clinical outcomes. Many of these chromosomal translocations result in novel fused genes. We hypothesize that these fused genes induce aberrant gene expression patterns and that this is the mechanism by which these translocations contribute to the development of leukemia and, consequently, affect prognosis. However, not all of the heterogeneity in clinical outcome can be explained by translocations. We hypothesize that other specific heterogeneous features of ALL, such as variable response to chemotherapeutic agents, are also reflected in distinct patterns of gene expression. The broad goals of the project described in this proposal are to use measurements of the expression levels of a large number of genes in ALL to gain a better understanding of specific features of ALL. In order to make such measurements, we will exploit recently developed high-density cDNA microarray technology. The specific aims of this project are: (1) to identify distinct patterns of gene expression that are associated with particular chromosomal t r anslocations, (2) to identify distinct patterns of gene expression associated with sensitivity or resistance to chemotherapy, (3) to use gene expression measurements to identify important diagnostic and prognostic subtypes of ALL, that have not previously been recognized, and (4) to develop testable models for the gene transcription pathways involved in ALL. Through this work, we expect to make a number of important contributions to the understanding of ALL. First, we will gain a deeper understanding of the molecular mechanisms responsible for the development of ALL. Second, we will gain insight into the mechanisms of chemotherapy resistance in ALL and, thus, facilitate the development of methods to overcome this resistance. Third, through the identification of previously unrecognized subtypes of ALL, we expect to facilitate the development of novel, clinically useful markers to guide treatment in this disease. Fourth, by exploiting novel modeling techniques, we expect to gain a deeper understanding of the gene transcription networks that are important in ALL.