Evaluation of the sirtuin isoform expression pattern in childhood acute lymphoblastic und childhood acute myeloid leukaemia.

儿童急性淋巴细胞白血病和儿童急性髓性白血病中沉默调节蛋白亚型表达模式的评估。

基本信息

批准号：
208154129
负责人：
Professor Dr. James Beck
金额：
--
依托单位：
Klinik für Kinder- und Jugendmedizin
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2011
资助国家：
德国
起止时间：
2010-12-31 至 2014-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/208154129?language=en
关键词：
Evaluation sirtuin isoform expression pattern

项目摘要

Reversible acetylation of histones and non-histone proteins is one of the most frequent posttranslational modifications in eukaryotic cells. The importance of aberrant protein acetylation - in particular of histones - in human cancer development is becoming increasingly clear. Protein acetylation and deacetylation are catalysed by the opposite activities of two enzyme families, the histone acetyltransferases and the histone deacetylases (HDAC). Abnormal expression of HDAC has been observed in a wide range of cancer types, and, thus, HDAC are considered as promising drug targets in anticancer therapy.The HDAC family, which comprises 18 isoforms, is divided into five phylogenetic classes. The eleven isoforms belonging to class I, IIa, IIb and IV are termed "HDAC" in a narrower sense (HDAC1-11), whilst the seven isoforms belonging to class III are termed "sirtuins" (SIRT1-7). HDAC and sirtuins are biochemically and pharmacologically unrelated; importantly, SIRT1-7 are not affected by HDAC inhibitors (HDACi), and HDAC1-11 are not affected by sirtuin inhibitors (SIRTi).So far our investigations have focused on the HDAC isoforms belonging to class I, IIa, IIb and IV, i.e. the HDAC1-11, and not touched the class III isoforms, the sirtuins. However, recent in vitro findings point to a relevant role of the sirtuins in neoplastic transformation. Yet clinical data on sirtuins are scarce, and childhood leukaemias have not at all been investigated. Therefore, our new project aims at evaluating the clinical relevance of sirtuins in childhood acute lymphoblastic (ALL) and acute myeloid leukaemia (AML). It shall proceed according to our ongoing project on HDAC1-11. The mRNA expression of SIRT1-7 shall be determined by real-time RT-PCR in samples from ALL and AML patients and samples from healthy donors. Aberrant expression levels of individual sirtuins will be analysed for association with clinicopathological parameters. Potentially clinically significant SIRT isoforms will be validated in vitro. This project promises to yield insight into the role of sirtuins in childhood leukaemias and to provide a rationale for the development of sirtuin-targeted agents as antileukaemic drugs.

组蛋白和非组蛋白的可逆乙酰化是真核细胞中最常见的翻译后修饰之一。异常蛋白质乙酰化（尤其是组蛋白）在人类癌症发展中的重要性正变得越来越明显。蛋白质乙酰化和脱乙酰化由组蛋白乙酰转移酶和组蛋白脱乙酰酶 (HDAC) 这两个酶家族的相反活性催化。 HDAC 的异常表达已在多种癌症类型中观察到，因此，HDAC 被认为是抗癌治疗中有前途的药物靶点。HDAC 家族包含 18 个亚型，分为 5 个系统发育类别。属于 I、IIa、IIb 和 IV 类的 11 种异构体被称为狭义的“HDAC”(HDAC1-11)，而属于 III 类的 7 种异构体被称为“sirtuins”(SIRT1-7)。 HDAC 和 Sirtuins 在生化和药理学上不相关；重要的是，SIRT1-7 不受 HDAC 抑制剂 (HDACi) 的影响，HDAC1-11 不受沉默调节蛋白抑制剂 (SIRTi) 的影响。到目前为止，我们的研究主要集中在属于 I、IIa、IIb 和 IV 类的 HDAC 亚型，即 HDAC1-11，并且没有触及 III 类亚型，sirtuins。然而，最近的体外研究结果表明去乙酰化酶在肿瘤转化中具有相关作用。然而，sirtuins 的临床数据很少，而且根本没有对儿童白血病进行过研究。因此，我们的新项目旨在评估去乙酰化酶在儿童急性淋巴细胞（ALL）和急性髓性白血病（AML）中的临床相关性。它将根据我们正在进行的 HDAC1-11 项目进行。应通过实时 RT-PCR 测定 ALL 和 AML 患者样本以及健康供体样本中 SIRT1-7 的 mRNA 表达。将分析个体去乙酰化酶的异常表达水平与临床病理学参数的关联。具有潜在临床意义的 SIRT 同工型将在体外得到验证。该项目有望深入了解去乙酰化酶在儿童白血病中的作用，并为开发去乙酰化酶靶向药物作为抗白血病药物提供理论依据。