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.

组蛋白和非内酮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。异常蛋白乙酰化（特别是组蛋白）在人类癌症发育中的重要性变得越来越清楚。蛋白质乙酰化和脱乙酰化是由两个酶家族，组蛋白乙酰转移酶和组蛋白脱乙酰基酶（HDAC）的相反活性催化的。在广泛的癌症类型中已经观察到HDAC异常表达，因此，HDAC被认为是抗癌治疗中有希望的药物靶标。组成18同工型的HDAC家族分为五个系统发育类别。属于I类，IIA，IIB和IV的11种同工型以较窄的意义（HDAC1-11）称为“ HDAC”，而属于III类的七种同工型被称为“ Sirtuins”（Sirtuins”（SIRT1-7）。 HDAC和SIRTUIN在生化和药理学上无关。重要的是，SIRT1-7不受HDAC抑制剂（HDACI）的影响，而HDAC1-11不受SIRTUIN抑制剂的影响（SIRTI）。因此，我们的研究集中在属于I，IIA，IIA，IIB和IV类的HDAC同工型上，即IIA，IIB和IV，即HDAC1-1-1-1-1-1-1-1-1-1-1-11，以及III III III III III III III III III III。但是，最近的体外发现表明Sirtuins在肿瘤转化中的相关作用。然而，关于Sirtuins的临床数据很少，童年白血病尚未得到研究。因此，我们的新项目旨在评估Sirtuins在儿童期急性淋巴细胞（ALL）和急性髓样白血病（AML）中的临床相关性。它应根据我们在HDAC1-11上正在进行的项目进行。 SIRT1-7的mRNA表达应由来自健康供体的所有和AML患者的样品以及样本中的实时RT-PCR确定。将分析单个Sirtuins的异常表达水平，以与临床病理学参数关联。潜在具有临床意义的SIRT同工型将在体外进行验证。该项目有望深入了解Sirtuins在儿童白血病中的作用，并为开发以Sirtuin靶向药物为抗肺部药物提供理由。