Quantitative HOX Expression as Prognostic Marker in AML

定量 HOX 表达作为 AML 的预后标志物

• 批准号: 6844440
• 负责人: HARRY A. DRABKIN
• 金额: $ 31.02万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-20 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6844440
• 关键词: acute myelogenous leukemia; analytical method; clinical research; cytogenetics; gene expression; genetic markers; homeobox genes; human genetic material tag; human tissue; method development; neoplasm /cancer genetics; polymerase chain reaction; prognosis

DESCRIPTION (provided by applicant): Homeodomain containing genes encode transcription factors that act during development to control pattern formation, differentiation and proliferation. Based on data from our laboratory and work of others, the quantitative analysis of HOX gene expression promises to be a powerful new tool in the prognostic assessment of patients with acute myelogenous leukemia (AML). To date, characteristic chromosomal alterations have been the gold standard for prognosis in AML. However, 50 percent of AML patients lack cytogenetic changes and another 10-20 percent have alterations considered to be of intermediate importance. Thus, a majority of patients with AML lack sufficient prognostic markers upon which definitive therapeutic decisions can be made. Our studies indicate that the patterns of quantitative HOX gene expression are in near total concordance with favorable and adverse chromosomal features. In addition, these expression patterns extend to the subset of patients with normal cytogenetics and other intermediate changes and are predictive of outcome. We propose to confirm and extend our initial observations on the importance of HOX gene expression in AML. In the R21, we will refine our quantitative assays to include the complete set of HOXA, HOXB and important TALE (PBX, MEIS) family members and validate the analytic performance of these assays. We will also explore the analysis of selected extended HOX and paraHox genes in AML for inclusion in the subsequent R33. The R33 phase will determine the role of quantitative HOX expression as a prognostic marker in AML, the association of HOX expression patterns with specific chromosomal features as well as resistant or relapsed disease, and should permit us to identify the most useful subset of HOX genes based on our analysis of large numbers of patients and disease phenotypes. Lastly, we will determine whether there is a relationship between HOX expression and another new predictor of outcome involving internal tandem duplications or mutations of the FLT3 receptor. Importantly, the HOX genes are more than markers of lineage, or differentiation. Rather, they are integrally involved in the pathogenesis of acute leukemia in both mice and man. Thus, their analysis provides insight into the disease process, and its heterogeneity, while providing new important prognostic information.

描述（由申请人提供）： 含有同源结构域的基因编码转录因子，这些转录因子在 发育以控制模式形成、分化和增殖。 根据我们实验室的数据和其他人的工作，定量 HOX基因表达分析有望成为一个强大的新工具 急性髓性白血病（AML）患者的预后评估。到 迄今为止，特征性染色体改变已成为黄金标准 AML 的预后。然而，50% 的 AML 患者缺乏细胞遗传学改变 另外 10-20% 的改变被认为是中等程度的 重要性。因此，大多数 AML 患者缺乏足够的预后 可以根据这些标记做出明确的治疗决定。我们的研究 表明 HOX 基因定量表达模式接近 有利和不利染色体特征的完全一致性。在 此外，这些表达模式延伸到患有以下疾病的患者子集： 正常的细胞遗传学和其他中间变化并且可以预测 结果。我们建议确认并扩展我们对 HOX 基因表达在 AML 中的重要性。在R21中，我们将完善我们的 定量分析包括全套 HOXA、HOXB 和重要的 TALE（PBX、MEIS）家族成员并验证这些成员的分析性能 化验。我们还将探索对选定的扩展 HOX 和 paraHox 的分析 AML 中的基因包含在后续的 R33 中。 R33相将决定 定量 HOX 表达作为 AML 预后标志物的作用 HOX表达模式与特定染色体特征的关联 以及耐药性或复发性疾病，并且应该允许我们识别 基于我们对大量 HOX 基因的分析，最有用的 HOX 基因子集 患者和疾病表型。最后我们要判断是否存在 HOX表达与另一个新的结果预测因子之间的关系 涉及 FLT3 受体的内部串联重复或突变。 重要的是，HOX 基因不仅仅是谱系标记，或者 差异化。相反，它们整体参与了疾病的发病机制。 小鼠和人的急性白血病。因此，他们的分析提供了见解 深入了解疾病过程及其异质性，同时提供新的重要信息 预后信息。