Acute myeloid leukemia (AML) is a phenotypically and prognostically heterogeneous hematopoietic stem cell disease that may be cured in eligible patients with intensive chemotherapy and/or allogeneic stem cell transplantation (allo-SCT). Tremendous advances in sequencing technologies have revealed a large amount of molecular information which has markedly improved our understanding of the underlying pathophysiology and enables a better classification and risk estimation. Furthermore, with the approval of the FMS-like tyrosine kinase 3 (FLT3) inhibitor Midostaurin a first targeted therapy has been introduced into the first-line therapy of younger patients with FLT3-mutated AML and several other small molecules targeting molecular alterations such as isocitrate dehydrogenase (IDH) mutations or the anti-apoptotic b-cell lymphoma 2 (BCL-2) protein are currently under investigation. Despite these advances, many patients will have to undergo allo-SCT during the course of disease and depending on disease and risk status up to half of them will finally relapse after transplant. Here we review the current knowledge about the molecular landscape of AML and how this can be employed to prevent, detect and treat relapse of AML after allo-SCT.

Graphene quantum dots (GQDs) are a promising next generation nanomaterial with manifold biomedical applications. For real world applications, comprehensive studies on their influence on the functionality of primary human cells are mandatory. Here, we report the effects of GQDs on the transcriptome of CD34⁺hematopoietic stem cells after an incubation time of 36 hours. Of the 20 800 recorded gene expressions, only one, namely the selenoprotein W, 1, is changed by the GQDs in direct comparison to CD34⁺hematopoietic stem cells cultivated without GQDs. Only a meta analysis reveals that the expression of 1171 genes is weakly affected, taking into account the more prominent changes just by the cell culture. Eight corresponding, weakly affected signaling pathways are identified, which include, but are not limited to, the triggering of apoptosis. These results suggest that GQDs with sizes in the range of a few nanometers hardly influence the CD34⁺cells on the transcriptome level after 36 h of incubation, thereby demonstrating their high usability forin vivostudies, such as fluorescence labeling or delivery protocols, without strong effects on the functional status of the cells.

Background: Dendritic cell (DC) vaccines can induce antitumor immune responses in patients with malignant diseases, while the most suitable DC culture conditions have not been established yet. In this study we compared monocyte derived human DC from conventional cultures containing GM-CSF and IL-4/TNF-α (IL-4/TNF-DC) with DC generated by the novel protocol using GM-CSF and IFN-α (IFN-DC).Methods: To characterise the molecular differences of both DC preparations, gene expression profiling was performed using Affymetrix microarrays. The data were conformed on a protein level by immunophenotyping, and functional tests for T cell stimulation, migration and cytolytic activity were performed.Results: Both methods resulted in CD11c+ CD86+ HLA-DR+ cells with a typical DC morphology that could efficiently stimulate T cells. But gene expression profiling revealed two distinct DC populations.Whereas IL-4/TNF-DC showed a higher expression of genes envolved in phagocytosis IFN-DC had higher RNA levels for markers of DC maturity and migration to the lymph nodes like DCLAMP, CCR7 and CD49d. This different orientation of both DC populations was confined by a 2.3 fold greater migration in transwell experiments (p = 0.01).Most interestingly, IFN-DC also showed higher RNA levels for markers of NK cells such as TRAIL, granzymes, KLRs and other NK cell receptors. On a protein level, intracytoplasmatic TRAIL and granzyme B were observed in 90% of IFN-DC. This translated into a cytolytic activity against K562 cells with a median specific lysis of 26% at high effector cell numbers as determined by propidium iodide uptake, whereas IL-4/TNF-DC did not induce any tumor cell lysis (p = 0.006). Thus, IFN-DC combined characteristics of mature DC and natural killer cells.Conclusion: Our results suggest that IFN-DC not only stimulate adaptive but also mediate innate antitumor immune responses. Therefore, IFN-DC should be evaluated in clinical vaccination trials. In particular, this could be relevant for patients with diseases responsive to a treatment with IFN-α such as Non-Hodgkin lymphoma or chronic myeloid leukemia.

The amyloid fibril formation by $\alpha$ -synuclein is a hallmark of various neurodegenerative disorders, most notably Parkinson’s disease. Epigallocatechin gallate (EGCG) has been reported to be an efficient inhibitor of amyloid formation by numerous proteins, among them $\alpha$ -synuclein. Here, we show that this applies only to a small region of the relevant parameter space, in particular to solution conditions where EGCG readily oxidizes, and we find that the oxidation product is a much more potent inhibitor compared to the unmodified EGCG. In addition to its inhibitory effects, EGCG and its oxidation products can under some conditions even accelerate $\alpha$ -synuclein amyloid fibril formation through facilitating its heterogeneous primary nucleation. Furthermore, we show through quantitative seeding experiments that, contrary to previous reports, EGCG is not able to re-model $\alpha$ -synuclein amyloid fibrils into seeding-incompetent structures. Taken together, our results paint a complex picture of EGCG as a compound that can under some conditions inhibit the amyloid fibril formation of $\alpha$ -synuclein, but the inhibitory action is not robust against various physiologically relevant changes in experimental conditions. Our results are important for the development of strategies to identify and characterize promising amyloid inhibitors.

Human leukocytes obtained from samples of leukapheresis products of three healthy donors stimulated by granulocyte colony stimulating factor (G-CSF) were exposed to graphene quantum dots. A time- and concentration dependent uptake was observed with a significantly greater uptake into monocytes and granulocytes in comparison to lymphocytes, suggesting a better incorporation ability of cells with phagocytotic properties. The uptake rates also correlate with the cell membrane area. Looking at the different lymphoid subsets a greater uptake was found into CD19⁺ B-, CD56⁺ natural killer cells and CD34⁺ hematopoietic stem cells (HSC) in comparison to CD4⁺ T- and CD8⁺ T cells. Independent of the cell type studied, the observed uptake dynamics is consistent with a diffusion-driven process, which allows the determination of cell-specific membrane permeabilities for the graphene quantum dots. The toxicity of the quantum dots is relatively low resulting in a 90% viability of the entire leukocyte population after 36 hours of exposure to GQDs at a concentration of 500 μg ml⁻¹.