Abstract
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.
Highlights
Transcriptional regulation of the megakaryocyte/erythroid (ME) lineage is regulated by a relatively small number of master regulators
Since KDACi are effective in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), this suggests that the regulation of protein acetylation is involved in aberrant cellular differentiation in malignancies, as well as normal myeloid differentiation
In this study, utilising an ex-vivo human CD34+ differentiation system, we investigated the effects of valproic acid (VPA), a widely used class I, and to a lesser extent, class IIa KDACi [58, 59], and the SIRT1/2 inhibitor NAM on normal megakaryocyte development
Summary
Transcriptional regulation of the megakaryocyte/erythroid (ME) lineage is regulated by a relatively small number of master regulators. KDAC and SIRT inhibition modulates megakaryopoiesis (CMP) towards the ME-lineage in humans is mainly regulated by GATA-1, the key-regulator of both megakaryocyte, and erythrocyte development [1,2,3]. Progression from the megakaryocyte/erythroid progenitor (MEP) towards megakaryocyte differentiation involves the activity of Runt-related transcription factor 1 (RUNX1, or AML1), LIM domain only 2 (LMO2), nuclear factor, erythroid-derived 2 (NF-E2), and Friend leukaemia integration 1 (Fli-1), which regulates the expression of late stage megakaryocyte markers [4,5,6,7]. While previous studies have suggested a role for genes involved in cell cycle regulation and cytokinesis, including survivin and Aurora B, the regulation of polyploidisation remains unclear [8,9,10,11]
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