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

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清楚。蛋白质乙酰化和去乙酰化是由两个酶家族——组蛋白乙酰转移酶和组蛋白去乙酰化酶（HDAC）——的相反活性催化的。HDAC的异常表达已在多种癌症类型中被观察到，因此，HDAC被认为是抗癌治疗中有前景的药物靶点。HDAC家族由18个亚型组成，分为5个系统发育类。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在生物化学和药理学上是不相关的；重要的是，SIRT1-7不受HDAC抑制剂（HDACi）的影响，HDAC1-11不受sirtuin抑制剂（SIRTi）的影响。到目前为止，我们的研究主要集中在HDAC的I类、IIa类、IIb类和IV类亚型，即HDAC1-11，而没有触及III类亚型，即sirtuins。然而，最近的体外研究结果指出了sirtuins在肿瘤转化中的相关作用。然而，关于sirtuins的临床数据很少，儿童白血病根本没有被调查过。因此，我们的新项目旨在评估sirtuins在儿童急性淋巴细胞（ALL）和急性髓性白血病（AML）中的临床意义。按照我们正在进行的HDAC1-11项目进行。采用实时RT-PCR检测ALL、AML患者和健康供者样本中SIRT1-7 mRNA的表达。将分析单个sirtuins的异常表达水平与临床病理参数的关系。具有潜在临床意义的SIRT亚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sirtuins靶向抗白血病药物的开发提供理论依据。

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.