Experimental confirmation of efficient island divertor operation and successful neoclassical transport optimization in Wendelstein 7-X

We present recent highlights from the most recent operation phases of Wendelstein 7-X, the most advanced stellarator in the world. Stable detachment with good particle exhaust, low impurity content, and energy confinement times exceeding 100 ms, have been maintained for tens of seconds. Pellet fueling allows for plasma phases with reduced ion-temperature-gradient turbulence, and during such phases, the overall confinement is so good (energy confinement times often exceeding 200 ms) that the attained density and temperature profiles would not have been possible in less optimized devices, since they would have had neoclassical transport losses exceeding the heating applied in W7-X. This provides proof that the reduction of neoclassical transport through magnetic field optimization is successful. W7-X plasmas generally show good impurity screening and high plasma purity, but there is evidence of longer impurity confinement times during turbulence-suppressed phases.EC/H2020/633053/EU/Implementation of activities described in the Roadmap to Fusion during Horizon 2020 through a Joint programme of the members of the EUROfusion consortium/ EUROfusio

ABR, a novel inducer of transcription factor C/EBPα, is necessary for myeloid differentiation and a favorable prognostic factor in acute myeloid leukemia

Introduction: Active BCR related (ABR) protein is closely homologous to BCR, which acts as a tumor suppressor in leukemia. Repression of ABR expression has been reported in t(8;21) acute myeloid leukemia (AML). However, the specific function of ABR in myeloid differentiation or AML has not been studied yet. Methods: We utilized acute myeloid leukemia U937 cell line, mouse bone marrow cells and human bone marrow cells from patients with acute myeloid leukemia. Cell differentiation was assessed by flow cytometry. Cell-cycle analysis was performed with propidium iodide and analyzed by flow cytometry. RNA detection was performed by quantitative real-time PCR. Protein detection was performed by immunoblot analyses. Trans¬fections of constructs pEYFP-ABR, pcDNA3.1-E2F1, ABR siRNA or CE¬BPA siRNA in U937 cells were performed via electroporation. Results: We observed highly reduced ABR mRNA in AML patients from different karyotypes. Moreover, AML patients with high ABR expression survive significantly longer after hematopoietic stem cell transplantation. Here we found for the first time that older patients with AML that have high ABR expression benefited from azacytidine treatment, presenting an early response. Furthermore, treatment of leukemic cells with azacytidine induces ABR expression. ABR expression is increased while M-CSF and G-CSF stimulated myeloid differentiation of mouse bone marrow cells. In contrast to this, siRNA mediated block of ABR prevents myeloid differen¬tiation. We identified ABR as a novel player in myelopoiesis via increasing the expression of the myeloid transcription factor C/EBPα, a major regu¬lator of myeloid differentiation and functionally impaired in leukemia. Fi¬nally, ABR blocks cell-cycle progression and downregulates the cell-cycle activator E2F1, indicating the functional role of ABR as tumor suppressor in leukemic cells. Conclusions: Taken together, our data demonstrate that ABR plays a crit¬ical role in myelopoiesis via inducing C/EBPα and indicate the strong tu¬mor suppressor potential of ABR expression in AML. Targeted treatments that increase endogenous levels of ABR might represent novel therapeutic strategies

Disruption of the C/EBP? - MiR-182 balance impairs granulocytic differentiation

10.1038/s41467-017-00032-6Nature Communications813

Disturbance of the C/EBP alpha-miR-182 balance impairs granulocytic differentiation and promotes development of acute myeloid leukemia

Introduction: Silencing of major myeloid transcription factor C/EBPa by gene mutation, promoter hypermethylation or posttranslational modifications is well described and occurs in ~50% of acute myeloid leukemia (AML) cases. Deregulation of C/EBPa by microRNAs, a class of small non-coding RNAs, as a substantial event during AML development or during myeloid differentiation has not been studied yet. Methods: We screened for C/EBPa dependent miRNAs in inducible K562-C/EBPa-ER cells using Illumina’s Next Generation Sequencing. For in vitro functional studies including gain-of-function and loss-of-function experiments, we utilized common acute myeloid leukemia cell lines, human hematopoietic stem cells from umbilical cord blood, murine hematopoietic stem cells from mouse bone marrow and primary human cells from patients with acute myeloid leukemia. For in vivo investigations, we manipulated Lin-Sca-1+c-Kit+ (LSK) murine hematopoietic progenitor cells by lentiviral infection and transplanted them into lethally irradiated littermates. The resulting phenotype was analyzed by flow cytometry and morphological staining of blood and bone marrow. Results: We identified oncogenic miR-182 as strong regulator of C/EBPa during myeloid differentiation and in AML. Moreover, we uncovered a novel regulatory loop between C/EBPa and miR-182. While C/EBPa blocks miR-182 expression by direct promoter binding during myeloid differentiation, enforced expression of miR-182 leads to reduced C/EBPa protein levels and impairs granulopoiesis in vitro and in a transplantation based mouse model in vivo. In contrast to this, a knockdown of miR-182 expression enhances C/EBPa protein levels in human AML. Furthermore, we observed highly elevated miR-182 expression levels particularly in AML patients with C-terminal CEBPA mutations and thereby uncovered a mechanism how C/EBPa blocks miR-182 expression. Finally by evaluation of TCGA database, we identified miR-182 expression as a strong adverse prognostic factor in cytogenetically high risk AML patients. Conclusions: Taken together, our data demonstrate the importance of a controlled balance between C/EBPa and miR-182 for the maintenance of healthy granulopoiesis and might uncover a novel mechanism for potential treatment strategies in AML. Disclosure: No conflict of interest disclosed