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涉及获取染色体 DNA 和随后的基因转录的细胞过程的调节中发挥着至关重要的作用。这些过程在很大一部分癌症中不受调节，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 发生和进展的影响，我们打算开发用于筛选 AML 和 CLL 特异性组蛋白修饰模式的测定方法，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定组蛋白亚型及其对患者预后的影响。此外，我们将描述 HDAC 抑制剂诱导的组蛋白修饰的变化，这些变化与 AML 和 CLL 细胞体外和体内细胞凋亡和分化的诱导相关。然后，这些发现将应用于从接受组蛋白脱乙酰酶抑制剂缩肽和我们的临床小组使用的其他可能的组蛋白脱乙酰酶抑制剂的受试者获得的患者肿瘤细胞样本，以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组蛋白中观察到的特定翻译后变化，并使临床翻译科学家能够有效预测结果并应用针对 AML 和 CLL 患者改变这些结果的疗法。

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.