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

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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.