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Leukemia. 2017 Dec;31(12):2732-2741. doi: 10.1038/leu.2017.137. Epub 2017 May 9.

MicroRNA-146a reduces MHC-II expression via targeting JAK/STAT signaling in dendritic cells after stem cell transplantation.

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Department of Hematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Spemann Graduate School of Biology and Medicine, ALU Freiburg, Germany.
Faculty of Biology, ALU Freiburg, Germany.
Signal Transduction in Tumour Development and Drug Resistance Group, Institute of Molecular Medicine and Cell Research (IMMZ), ALU Freiburg, Germany.
Department of Pathology, Freiburg University Medical Center, ALU Freiburg, Germany.
Centre for Biological Signaling Studies BIOSS, ALU Freiburg, Germany.
Medical Clinic III, Oncology, Hematology and Rheumatology, University Hospital Bonn (UKB), Bonn, Germany.
German Cancer Consortium (DKTK), Freiburg, Germany.
German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Medicine, Hematology and Medical Oncology, Mount Sinai Hospital, New York, NY, USA.
Center for Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Germany.
Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Germany.


Acute Graft-versus-host disease (GVHD) is a major immunological complication after allogeneic hematopoietic cell transplantation and a better understanding of the molecular regulation of the disease could help to develop novel targeted therapies. Here we found that a G/C polymorphism within the human microRNA-146a (miR-146a) gene of transplant recipients, which causes reduced miR-146a levels, was strongly associated with the risk of developing severe acute GVHD (n=289). In mice, deficiency of miR-146a in the hematopoietic system or transfer of recipient-type miR-146a-/- dendritic cells (DCs) enhanced GVHD, while miR-146a mimic-transfected DCs ameliorated disease. Mechanistically, lack of miR-146a enhanced JAK2-STAT1 pathway activity, which led to higher expression of class II-transactivator (CIITA) and consecutively increased MHCII-levels on DCs. Inhibition of JAK1/2 or CIITA knockdown in DCs prevented miR-146a-/- DC-induced GVHD exacerbation. Consistent with our findings in mice, patients with the miR-146a polymorphism rs2910164 in hematopoietic cells displayed higher MHCII levels on monocytes, which could be targeted by JAK1/2 inhibition. Our findings indicate that the miR-146a polymorphism rs2910164 identifies patients at high risk for GVHD before allo-HCT. Functionally we show that miR-146a acts as a central regulator of recipient-type DC activation during GVHD by dampening the pro-inflammatory JAK-STAT/CIITA/MHCII axis, which provides a scientific rationale for early JAK1/2 inhibition in selected patients.

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