Di(2-ethylhexyl)phthalate impairs erythropoiesis via inducing Klotho expression and not via bioenergetic reprogramming.

Di(2-ethylhexyl)phthalate (DEHP) is the most widely used phthalate to manufacture various plastic products. However, the potential effects of DEHP on erythropoiesis have not been investigated comprehensively. Here, we aimed to investigate whether DEHP modulated the function of hematopoietic stem and progenitor cells (HSPCs) to influence erythropoiesis, and to explore the associated mechanisms. In the present study, human cell lines with a capacity to differentiate into erythroid cells and murine bone marrow cells were treated with DEHP. DEHP not only impaired HSPC function, but also suppressed erythroid differentiation in a dose-dependent manner. In addition, DEHP removal restored HSPC activity. To explore how DEHP interfered with erythroid differentiation, we focused on energy metabolism and Klotho expression. DEHP suppressed erythroid differentiation via upregulating Klotho expression, while it did not via modulating cellular bioenergetics. Therefore, our results provided a novel insight into the pathophysiological link between phthalates and dysregulated erythroid differentiation.

Glucosamine Interferes With Myelopoiesis and Enhances the Immunosuppressive Activity of Myeloid-Derived Suppressor Cells.

Glucosamine (GlcN) is the most widely consumed dietary supplement and exhibits anti-inflammatory effects. However, the influence of GlcN on immune cell generation and function is largely unclear. In this study, GlcN was delivered into mice to examine its biological function in hematopoiesis. We found that GlcN promoted the production of immature myeloid cells, known as myeloid-derived suppressor cells (MDSCs), both in vivo and in vitro. Additionally, GlcN upregulated the expression of glucose transporter 1 in hematopoietic stem and progenitor cells (HSPCs), influenced HSPC functions, and downregulated key genes involved in myelopoiesis. Furthermore, GlcN increased the expression of arginase 1 and inducible nitric oxide synthase to produce high levels of reactive oxygen species, which was regulated by the STAT3 and ERK1/2 pathways, to increase the immunosuppressive ability of MDSCs. We revealed a novel role for GlcN in myelopoiesis and MDSC activity involving a potential link between GlcN and immune system, as well as the new therapeutic benefit.

The extracellular signal-regulated kinase 1/2 modulates the intracellular localization of DNA methyltransferase 3A to regulate erythrocytic differentiation.

DNA methylation, catalyzed by DNA methyltransferases (DNMTs), is a heritable epigenetic mark, participating in numerous physiological processes. DNMT3A is of particular relevance to hematopoietic differentiation, because DNMT3A mutations are strongly related to hematopoietic malignancies. Additionally, DNMT3A deficiency has been reported to increase the hematopoietic stem cell pool by limiting their differentiation. Our previous study demonstrated that complete loss of DNMT3A resulted in anemia, while DNMT3A haploinsufficiency caused an elevated population of erythrocytes in the content of oncogenic KRAS. Since erythropoiesis is tightly regulated via the erythropoietin (EPO)-mediated RAS-RAF-MEK-ERK1/2 pathway, the question arises whether DNMT3A cooperates with RAS signaling to modulate erythropoiesis. Human leukemia cell lines were used, with differentiation capabilities towards megakaryocyte and erythroid lineages. Overexpression of DNMT3A was found to enhance erythrocytic differentiation of K562 cells, while DNMT3A knockdown suppressed differentiation. Furthermore, higher DNMT3A expression was detected in late-stage mouse erythroblasts along with the DNMT3A translocation to the nucleus. Further studies demonstrated that both ERK1/2-DNMT3A interaction and serine-255 phosphorylation in DNMT3A led to DNMT3A translocation into the nucleus, and modulated erythrocytic differentiation. Our results not only explore the critical role of DNMT3A in erythropoiesis, but also provide a new insight into ERK1/2-DNMT3A interaction in the hematopoietic system.