Steering myelopoiesis

Summary

Epigenetic changes have been identified as important factors in the pathogenesis of haematological malignancies, which has resulted in a rapid increase in the use of chromatin modulating drugs, including lysine deacetylase inhibitors (KDACi, or histone deacetylase (HDAC) inhibitors). While the effects of KDACi on histone acetylation resulting in chromatin remodelling and subsequent activation of the transcriptional machinery have been studied extensively, the regulation of acetylation of non-histone proteins, in the context of disease, is not well understood. Since KDACi have proven to be very effective in myeloid disorders, including myelodysplastic syndrome (MDS), and acute myeloid leukemie (AML), this suggests that the regulation of protein acetylation plays an important role in aberrant myeloid differentiation, and raises questions as to the role of protein acetylation in normal myelopoiesis. It is therefore important to define the effects of this family of compounds on the normal hematopoietic compartment. In this thesis we sought to investigate the effects of KDACi in normal hematopoiesis, focusing on myeloid development towards the granulocyte/macrophage lineage, and megakaryocyte/erythroid lineage in order to increase our understanding of the effects of KDACi in myeloid disorders, regulation of their well-described molecular targets, and to identify novel protein substrates functionally regulated by acetylation during myeloid development. We report several novel findings including: i) KDAC inhibition regulates cell fate decisions during neutrophil development, which are distinct from the effects in malignant cells, (ii) the commonly used KDACi valproic acid (VPA) alters the proportion of leukocyte subsets in non-hematological patient groups, (iii) functional activity of the granulocyte-specific transcription factor C/EBPε is regulated by acetylation, and deacetylation, (iv) modulation of protein acetylation by class I/II KDAC, or class III KDAC/ SIRTi, differentially modulates megakaryocyte and erythroid development. In addition we report the effects of nitrostyrene derivatives, compounds most frequently studied as anti-cancer drugs, on the expansion and differentiation of myeloid progenitors, involving regulation of p38MAPK and C/EBPα activity, key regulators of myeloid development. Taken together, the knowledge concerning the role of epigenetic aberrancies in the pathogenesis of (myeloid) malignancies is increasing, resulting in a rapidly expanding research field focusing on the development of novel, targeted therapies. We have demonstrated that, in order to clinically use KDACi, and other epigenetic drugs, it is extremely important to define the effects of these compounds on normal hematopoiesis.

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