Quantitative HOX Expression as Prognostic Marker in AML

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 发展以控制图案的形成、分化和扩散。 根据我们实验室的数据和其他人的工作，量化 HOX基因表达分析有望成为一种强有力的新工具 急性髓系白血病(AML)患者的预后评估至 到目前为止，特征性的染色体改变一直是 急性髓系白血病的预后。然而，50%的AML患者缺乏细胞遗传学改变 另有10%-20%的人被认为是中级变化 重要性。因此，大多数AML患者缺乏足够的预后。 可以做出最终治疗决定的标记物。我们的研究 提示HOX基因的定量表达模式接近于 与有利和不利的染色体特征完全一致。在……里面 此外，这些表达模式延伸到患有 正常细胞遗传学和其他中间变化，并可预测 结果。我们建议确认并扩大我们对以下问题的初步观察 HOX基因表达在急性髓系白血病中的重要性在R21中，我们将完善我们的 定量分析包括全套HOXA、HOXB和重要 讲述(PBX、MEIS)家庭成员，并验证这些家庭成员的分析性能 化验。我们还将探讨选定的扩展Hox和ParaHox的分析 AML中的基因，以包括在随后的R33中。R33阶段将决定 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 以及耐药或复发的疾病，应该允许我们识别 最有用的HOX基因子集基于我们对大量 患者和疾病表型。最后，我们将确定是否存在 HOX表达与另一种新的预后预测因子的关系 涉及Flt3受体的内部串联复制或突变。 重要的是，HOX基因不仅仅是血统的标志，或者 差异化。相反，它们与糖尿病的发病机制密切相关。 小鼠和人都患有急性白血病。因此，他们的分析提供了洞察力 进入疾病的过程，及其异质性，同时提供了新的重要 预后信息。

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.