Dissecting the epigenomes and their impact on transcriptional regulation in normal and malignant granulopoiesis

Acute myeloid leukaemia (AML) is the most common form of acute leukaemia. It is characterised by high mortality and a long-term survival of only 15%. AML patients demonstrate a differentiation block in granulopoiesis, which results in an accumulation of immature blast cells in the bone marrow and peripheral blood. Despite the increased knowledge about AML the last decades, patients are most commonly treated with cytostatic drugs, which cause severe side effects. In order to develop safer therapeutics, better understanding of the mechanisms underlying this disease are needed.

Epigenetic mechanisms are deregulated in AML. Epigenetic regulatory enzymes are involved in both point mutations and chromosomal translocations. We hypothesise that epigenetic deregulation, which leads to perturbed histone modification, DNA methylation and chromatin remodeling causes the block in differentiation and increased cell proliferation in AML. The project aims at understanding the chromatin regulatory mechanisms and how they regulate transcription and consequently cell fate and differentiation. To be able to pinpoint abnormalities in leukaemia, thoroughly characterization of normal granulopoiesis is needed. By correlating histone modifications to, chromatin structure, DNA methylation and core promoter activity in both normal and malign granulopoiesis, abnormal alterations can be monitored. Thereby novel therapeutic targets can potentially be identified.