Semi‐arid grasslands on the Mongolian Plateau are expected to experience high inputs of anthropogenic reactive nitrogen in this century. It remains unclear, however, how soil organisms and nutrient cycling are directly affected by N enrichment (i.e., without mediation by plant input to soil) vs. indirectly affected via changes in plant‐related inputs to soils resulting from N enrichment. To test the direct and indirect effects of N enrichment on soil organisms (bacteria, fungi and nematodes) and their associated C and N mineralization, in 2010, we designated two subplots (with plants and without plants) in every plot of a six‐level N‐enrichment experiment established in 1999 in a semi‐arid grassland. In 2014, 4 years after subplots with and without plant were established, N enrichment had substantially altered the soil bacterial, fungal and nematode community structures due to declines in biomass or abundance whether plants had been removed or not. N enrichment also reduced the diversity of these groups (except for fungi) and the soil C mineralization rate and induced a hump‐shaped response of soil N mineralization. As expected, plant removal decreased the biomass or abundance of soil organisms and C and N mineralization rates due to declines in soil substrates or food resources. Analyses of plant‐removal‐induced changes (ratios of without‐ to with‐plant subplots) showed that micro‐organisms and C and N mineralization rates were not enhanced as N enrichment increased but that nematodes were enhanced as N enrichment increased, indicating that the effects of plant removal on soil organisms and mineralization depended on trophic level and nutrient status. Surprisingly, there was no statistical interaction between N enrichment and plant removal for most variables, indicating that plant‐related inputs did not qualitatively change the effects of N enrichment on soil organisms or mineralization. Structural equation modelling confirmed that changes in soil communities and mineralization rates were more affected by the direct effects of N enrichment (via soil acidification and increased N availability) than by plant‐related indirect effects. Our results provide insight into how future changes in N deposition and vegetation may modify below‐ground communities and processes in grassland ecosystems. A http://onlinelibrary.wiley.com/doi/10.1111/1365-2435.13226/suppinfo is available for this article.

PurposeAcute myeloid leukemia (AML) is a heterogeneous disease with poor outcomes. Despite increased evidence shows that dysregulation of histone modification contributes to AML, specific drugs targeting key histone modulators are not applied in the clinical treatment of AML. Here, we investigated whether targeting KDM6B, the demethylase of tri-methylated histone H3 lysine 27 (H3K27me3), has a therapeutic potential for AML.MethodsA KDM6B-specific inhibitor, GSK-J4, was applied to treat the primary cells from AML patients and AML cell lines in vitro and in vivo. RNA-sequencing was performed to reveal the underlying mechanisms of inhibiting KDM6B for the treatment of AML.ResultsHere we observed that the mRNA expression of KDM6B was up-regulated in AML and positively correlated with poor survival. Treatment with GSK-J4 increased the global level of H3K27me3 and reduced the proliferation and colony-forming ability of primary AML cells and AML cell lines. GSK-J4 treatment significantly induced cell apoptosis and cell-cycle arrest in Kasumi-1 cells, and displayed a synergistic effect with cytosine arabinoside. Notably, injection of GSK-J4 attenuated the disease progression in a human AML xenograft mouse model in vivo. Treatment with GSK-J4 predominantly resulted in down-regulation of DNA replication and cell-cycle-related pathways, as well as abrogated the expression of critical cancer-promoting HOX genes. ChIP-qPCR validated an increased enrichment of H3K27me3 in the transcription start sites of these HOX genes.ConclusionsIn summary, our findings suggest that targeting KDM6B with GSK-J4 has a therapeutic potential for the treatment of AML.Electronic supplementary materialThe online version of this article (10.1007/s00432-018-2631-7) contains supplementary material, which is available to authorized users.

Interleukin-27 (IL-27) is a novel cytokine of the IL-6/12 family with a broad range of immune regulation properties, which has been considered as a potential therapeutic agent for immune diseases and cancers. However, little is known about the effect of IL-27 on human neutrophils before its clinical administration. In this study, we investigated the effects of IL-27 on human neutrophil functions including adhesion, reactive oxygen species (ROS)/cytotoxic granule components production, inflammatory cytokines production, major histocompatibility complex (MHC) molecules expression and neutrophils' survival. We showed that IL-27 receptor complex, WSX-1/TCCR and gp130, is constitutively expressed on human neutrophils. In vitro, IL-27 suppressed neutrophil adhesion in response to fMLP, which might depend on the down-regulation of Mac-1. IL-27 also suppressed lipopolysaccharide-induced ROS production and attenuated cytotoxic granule components production in the cytoplasm of human neutrophils. In addition, IL-27 enhanced the production of IL-1β but not TNF-α from neutrophils. However, IL-27 failed to regulate the expression of MHC molecules and the survival of human neutrophils. In conclusion, our data demonstrate that IL-27 mainly down-modulates human neutrophil function, which might extend our understanding of the role of IL-27 in the innate immune response.

Fanconi anemia is a complex heterogeneous genetic disorder with a high incidence of bone marrow failure, clonal evolution to acute myeloid leukemia and mesenchymal-derived congenital anomalies. Increasing evidence in Fanconi anemia and other genetic disorders points towards an interdependence of skeletal and hematopoietic development, yet the impact of the marrow microenvironment in the pathogenesis of the bone marrow failure in Fanconi anemia remains unclear. Here we demonstrated that mice with double knockout of both Fancc and Fancg genes had decreased bone formation at least partially due to impaired osteoblast differentiation from mesenchymal stem/progenitor cells. Mesenchymal stem/progenitor cells from the double knockout mice showed impaired hematopoietic supportive activity. Mesenchymal stem/progenitor cells of patients with Fanconi anemia exhibited similar cellular deficits, including increased senescence, reduced proliferation, impaired osteoblast differentiation and defective hematopoietic stem/progenitor cell supportive activity. Collectively, these studies provide unique insights into the physiological significance of mesenchymal stem/progenitor cells in supporting the marrow microenvironment, which is potentially of broad relevance in hematopoietic stem cell transplantation.

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SummaryTET2 is a methylcytosine dioxygenase that regulates cytosine hydroxymethylation. Although there are extensive data implicating a pivotal role of TET2 in hematopoietic stem/progenitor cells (HSPCs), the importance of TET2 in bone marrow mesenchymal stromal cells (BMSCs) remains unknown. In this study, we show that loss of TET2 in BMSCs increases cell proliferation and self-renewal and enhances osteoblast differentiation potential of BMSCs, which may in turn alter their behavior in supporting HSPC proliferation and differentiation. In addition, Tet2 loss alters BMSCs in promoting Tet2-deficiency-mediated myeloid malignancy progression. Tet2 loss in BMSCs also dysregulates hydroxylation of 5-methylcytosine (5mC) and the expression of genes that are key for BMSC proliferation and osteoblast differentiation, leading to alteration of biological characteristics in vivo. These results highlight the critical role of TET2 in the maintenance of BMSC functions and osteoblast differentiation and provide evidence that dysregulation of epigenetic modifiers in BMSCs contributes to the progression of myeloid malignancies.

Aplastic anemia (AA) is a marrow failure syndrome mediated by aberrant T-cell subsets. Mesenchymal stem cells (MSCs) play an important role in maintaining immune homeostasis through modulating a variety of immune cells. However, little is known about the immunomodulation potential of bone marrow MSCs (BM-MSCs) in AA. Here, we reported that BM-MSCs from AA patients were reduced in suppressing the proliferation and clonogenic potential of CD4(+) T cells and the production of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), which was associated with decreased prostaglandin E2 (PGE2). Meanwhile, BM-MSCs from AA patients were defective to promote CD4(+)CD25(+)FOXP3(+) regulatory T cells expansion through reduced transforming growth factor-β (TGF-β). No significant difference between AA and normal BM-MSCs was observed in affecting the production of interleukins (IL)-4, IL-10 and IL-17. Our data indicate that BM-MSCs were impaired in maintaining the immune homeostasis associated with CD4(+) T cells, which might aggravate the marrow failure in AA.

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