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控中起着至关重要的作用，这些细胞过程涉及染色体DNA的获取和随后的基因转录。这些过程在很大比例的癌症中失调，包括两种最常见的成人白血病，急性髓性白血病（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，我们打算开发检测方法来筛选AML和CLL特异性组蛋白修饰模式，并进行详细的分子分析，以确定AML和CLL不同遗传亚型中存在的特异性组蛋白亚型及其对患者预后的影响。此外，我们将表征HDAC抑制剂诱导的组蛋白修饰的变化，这些变化与体外和体内AML和CLL细胞诱导凋亡和分化相关。这些发现随后将应用于从接受组蛋白去乙酰化酶抑制剂抑郁肽和潜在的其他组蛋白去乙酰化酶抑制剂的受试者中获得的患者肿瘤细胞样本，我们的临床小组使用这些样本来预测该疗法的早期治疗结果。因此，使用本提案中开发和验证的技术将使基础科学家能够了解在组蛋白中观察到的特定翻译后变化，并使临床转化科学家能够有效地预测结果并应用在AML和CLL患者中修改这些变化的治疗方法。

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.