| Autor: |
Bartels M; Center for Molecular Medicine and Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands.; Division of Pediatrics, University Medical Center Utrecht, Utrecht, the Netherlands., Govers A; Center for Molecular Medicine and Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands.; Division of Pediatrics, University Medical Center Utrecht, Utrecht, the Netherlands., Polak R; Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands., Vervoort S; Center for Molecular Medicine and Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands., van Boxtel R; Department of Developmental Biology and Stem Cell Research, Hubrecht Institute, Utrecht, the Netherlands., Pals C; Center for Molecular Medicine and Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands., Bierings M; Division of Pediatrics, University Medical Center Utrecht, Utrecht, the Netherlands., van Solinge W; Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, the Netherlands., Egberts T; Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, the Netherlands.; Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands., Nieuwenhuis E; Division of Pediatrics, University Medical Center Utrecht, Utrecht, the Netherlands., Mokry M; Division of Pediatrics, University Medical Center Utrecht, Utrecht, the Netherlands., Coffer PJ; Center for Molecular Medicine and Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, The Netherlands.; Division of Pediatrics, University Medical Center Utrecht, Utrecht, the Netherlands. |
| Abstrakt: |
Treatment with lysine deacetylase inhibitors (KDACi) for haematological malignancies, is accompanied by haematological side effects including thrombocytopenia, suggesting that modulation of protein acetylation affects normal myeloid development, and specifically megakaryocyte development. In the current study, utilising ex-vivo differentiation of human CD34+ haematopoietic progenitor cells, we investigated the effects of two functionally distinct KDACi, valproic acid (VPA), and nicotinamide (NAM), on megakaryocyte differentiation, and lineage choice decisions. Treatment with VPA increased the number of megakaryocyte/erythroid progenitors (MEP), accompanied by inhibition of megakaryocyte differentiation, whereas treatment with NAM accelerated megakaryocyte development, and stimulated polyploidisation. Treatment with both KDACi resulted in no significant effects on erythrocyte differentiation, suggesting that the effects of KDACi primarily affect megakaryocyte lineage development. H3K27Ac ChIP-sequencing analysis revealed that genes involved in myeloid development, as well as megakaryocyte/erythroid (ME)-lineage differentiation are uniquely modulated by specific KDACi treatment. Taken together, our data reveal distinct effects of specific KDACi on megakaryocyte development, and ME-lineage decisions, which can be partially explained by direct effects on promoter acetylation of genes involved in myeloid differentiation. |
