Epigenetic regulation of normal and aberrant myelopoiesis: a balancing act

Abstract

In the last two decades it has become increasingly evident that epigenetic changes are a contributing factor in aberrant myelopoiesis. Knowledge about epigenetic regulation of normal hematopoiesis is far from complete, however the use of chromatin modifying drugs has rapidly increased. Work in this thesis is aimed to increase understanding of the effects of epigenetic regulation and epigenetic modifiers on both normal and aberrant hematopoiesis. In Chapter 2, we investigated the role of acetylation of the transcription factor C/EPB in myelopoiesis. We found that acetylation of C/EBP is a prerequisite for normal neutrophil development. In Chapter 3, we investigated the effect of HDACi on megakaryocyte development. We found that manipulation of promotor acetylation by several HDACi (VPA and NAM) affected megakaryocyte development. Chapter 4 describes the effects of HDACi on normal hematopoiesis and especially neutrophil development. We investigated the transcriptomic, epigenomic, functional and morphological effects of two distinct HDACi, MS-275 and SAHA, in neutrophil development, providing insight into the regulatory mechanisms of HDACi. In Chapter 5, we performed a compound screen against epigenetic regulators to identify novel epigenetic drugs for the treatment of three types of pediatric AML; MLL-rearranged AML, CBF-arranged AML and acute megakaryoblastic AML in patients with Down syndrome (DS-AMKL). This identified potential therapeutic targets that could be of use in multiple pediatric AML subtypes. In Chapter 6, we have investigated the use of induced pluripotent stem cells (iPS) as an alternative source of human MSC, aiming to establish a standardised and easily replenishable source of MSC. Unfortunately, iPS-MSC did not prove to be a reproducible source of MSC for experimental use. Finally, Chapter 7, summarises the results and suggests future research that could address remaining and evolved questions from the work described in this thesis. Taken together, this thesis provides novel insights into the epigenetic of regulation of normal and malignant hematopoiesis. This knowledge can contribute to the development of novel epigenetic drugs for the treatment of myeloid malignancies.