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修饰是真核细胞中最常见的翻译后修饰之一。异常的蛋白质乙酰化-特别是组蛋白-在人类癌症发展中的重要性越来越清楚。蛋白质乙酰化和去乙酰化由两个酶家族的相反活性催化，即组蛋白乙酰转移酶和组蛋白去乙酰化酶（HDAC）。HDAC在多种肿瘤中异常表达，被认为是一种有前途的抗肿瘤药物靶点。HDAC家族由18种异构体组成，可分为5类。属于I类、IIa类、IIb类和IV类的11种同种型在狭义上称为“HDAC”（HDAC 1 -11），而属于III类的7种同种型称为“sirtuins”（SIRT 1 -7）。HDAC和sirtuins在生物化学上和生物学上不相关;重要的是，SIRT 1 -7不受HDAC抑制剂（HDACi）的影响，HDAC 1 -11不受sirtuin抑制剂（SIRTi）的影响。到目前为止，我们的研究集中在属于I类、IIa类、IIb类和IV类的HDAC亚型，即HDAC 1 -11，而没有触及III类亚型，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，儿童白血病也根本没有被研究过。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）中的临床相关性。它将根据我们正在进行的HDAC 1 -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SIRT 1 -7的mRNA表达。将分析个体沉默调节蛋白的异常表达水平与临床病理学参数的关联。将在体外验证具有潜在临床意义的SIRT亚型。该项目有望深入了解sirtuins在儿童白血病中的作用，并为开发sirtuins靶向药物作为抗白血病药物提供理论基础。

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.