Assays for Screening Histone Modification in Cancer

描述(由申请人提供)：核心组蛋白的翻译后修饰在细胞过程的调节中起着至关重要的作用，这些过程包括获得染色体DNA和随后的基因转录。这些过程在很大一部分癌症中是失控的，包括两种最常见的成人白血病，急性髓系白血病(AML)和慢性淋巴细胞白血病(CLL)。为了更好地了解这些修饰对AML和CLL的发展和进展的影响，我们打算开发筛选AML和CLL特异性组蛋白修饰模式的方法，并进行详细的分子分析，以确定AML和CLL不同基因亚型中存在的特定组蛋白亚型及其对患者预后的影响。此外，我们将在体外和体内研究与诱导AML和CLL细胞的凋亡和分化相关的HDAC抑制剂诱导的组蛋白修饰的变化。这些发现随后将应用于患者肿瘤细胞样本，这些样本来自受试者，受试者接受了我们临床小组使用的组蛋白去乙酰化酶抑制剂和潜在的其他组蛋白去乙酰化酶抑制剂，以预测这种疗法的早期治疗结果。因此，使用在这项建议中开发和验证的技术将使基础科学家能够了解在组蛋白蛋白中观察到的特定翻译后变化，临床翻译科学家将能够有效地预测结果，并在AML和CLL患者中应用改变这些变化的疗法。

DESCRIPTION (provided by applicant): The post-translational modification of the core histones plays a vital role in the regulation of cellular processes that involve access to chromosomal DNA and subsequent gene transcription. These processes are disregulated in a large proportion of cancers including the two most common types of adult leukemia, acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). To better understand the impact of these modifications on the development and progression of AML and CLL, we intend to develop assays for screening AML and CLL-specific patterns of histone modification and conduct a detailed molecular analysis to identify the specific histone isoforms present in different genetic subtypes of AML and CLL and their impact on patient outcome. Furthermore we will characterize the changes in the histone modification induced by HDAC inhibitors that correlate with induction of apoptosis and differentiation in vitro and in vivo in AML and CLL cells. These findings will then be applied to patient tumor cell samples obtained from subjects receiving the histone deacetylase inhibitor depsipeptide and potentially other histone deacetylase inhibitors used by our clinical group to predict early treatment outcome of this therapy. Thus, use of the techniques developed and validated in this proposal will allow basic scientists to understand specific post-translational changes observed in histone proteins and clinical-translational scientists to effectively predict outcome and apply therapies that modify these in patients with AML and CLL.