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      The AP-1-BATF and -BATF3 module is essential for growth, survival and TH17/ILC3 skewing of anaplastic large cell lymphoma

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      1 , 2 , 3 , 4 , 1 , 2 , 4 , 3 , 4 , 1 , 2 , 5 , 6 , 5 , 7 , 7 , 8 , 7 , 1 , 2 , 9 , 10 , 1 , 2 , 4 , 11 , 4 , 11 , 1 , 12 , 13 , 14 , 2 , 4 , 15 , 1 , 1 , 16 , 17 , 16 , 17 , 1 , 2 , 8 , 1 , 3 , 4 , 14 , 18 , 19 , , 1 , 2 , 20 , 1 , 2 , 4 , 8 , 20 ,
      Leukemia
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          Abstract

          Transcription factor AP-1 is constitutively activated and IRF4 drives growth and survival in ALK + and ALK anaplastic large cell lymphoma (ALCL). Here we demonstrate high-level BATF and BATF3 expression in ALCL. Both BATFs bind classical AP-1 motifs and interact with in ALCL deregulated AP-1 factors. Together with IRF4, they co-occupy AP-1-IRF composite elements, differentiating ALCL from non-ALCL. Gene-specific inactivation of BATFs, or global AP-1 inhibition results in ALCL growth retardation and/or cell death in vitro and in vivo. Furthermore, the AP-1-BATF module establishes TH17/group 3 innate lymphoid cells (ILC3)-associated gene expression in ALCL cells, including marker genes such as AHR, IL17F, IL22, IL26, IL23R and RORγt. Elevated IL-17A and IL-17F levels were detected in a subset of children and adolescents with ALK + ALCL. Furthermore, a comprehensive analysis of primary lymphoma data confirms TH17–, and in particular ILC3-skewing in ALCL compared with PTCL. Finally, pharmacological inhibition of RORC as single treatment leads to cell death in ALCL cell lines and, in combination with the ALK inhibitor crizotinib, enforces death induction in ALK + ALCL. Our data highlight the crucial role of AP-1/BATFs in ALCL and lead to the concept that some ALCL might originate from ILC3.

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          Most cited references49

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          IL-17 and Th17 Cells.

          CD4+ T cells, upon activation and expansion, develop into different T helper cell subsets with different cytokine profiles and distinct effector functions. Until recently, T cells were divided into Th1 or Th2 cells, depending on the cytokines they produce. A third subset of IL-17-producing effector T helper cells, called Th17 cells, has now been discovered and characterized. Here, we summarize the current information on the differentiation and effector functions of the Th17 lineage. Th17 cells produce IL-17, IL-17F, and IL-22, thereby inducing a massive tissue reaction owing to the broad distribution of the IL-17 and IL-22 receptors. Th17 cells also secrete IL-21 to communicate with the cells of the immune system. The differentiation factors (TGF-beta plus IL-6 or IL-21), the growth and stabilization factor (IL-23), and the transcription factors (STAT3, RORgammat, and RORalpha) involved in the development of Th17 cells have just been identified. The participation of TGF-beta in the differentiation of Th17 cells places the Th17 lineage in close relationship with CD4+CD25+Foxp3+ regulatory T cells (Tregs), as TGF-beta also induces differentiation of naive T cells into Foxp3+ Tregs in the peripheral immune compartment. The investigation of the differentiation, effector function, and regulation of Th17 cells has opened up a new framework for understanding T cell differentiation. Furthermore, we now appreciate the importance of Th17 cells in clearing pathogens during host defense reactions and in inducing tissue inflammation in autoimmune disease.
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            The anaplastic lymphoma kinase in the pathogenesis of cancer.

            Tyrosine kinases are involved in the pathogenesis of most cancers. However, few tyrosine kinases have been shown to have a well-defined pathogenetic role in lymphomas. The anaplastic lymphoma kinase (ALK) is the oncogene of most anaplastic large cell lymphomas (ALCL), driving transformation through many molecular mechanisms. In this Review, we will analyse how translocations or deregulated expression of ALK contribute to oncogenesis and how recent genetic or pharmacological tools, aimed at neutralizing its activity, can represent the basis for the design of powerful combination therapies.
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              Human Innate Lymphoid Cell Subsets Possess Tissue-Type Based Heterogeneity in Phenotype and Frequency.

              Animal models have highlighted the importance of innate lymphoid cells (ILCs) in multiple immune responses. However, technical limitations have hampered adequate characterization of ILCs in humans. Here, we used mass cytometry including a broad range of surface markers and transcription factors to accurately identify and profile ILCs across healthy and inflamed tissue types. High dimensional analysis allowed for clear phenotypic delineation of ILC2 and ILC3 subsets. We were not able to detect ILC1 cells in any of the tissues assessed, however, we identified intra-epithelial (ie)ILC1-like cells that represent a broader category of NK cells in mucosal and non-mucosal pathological tissues. In addition, we have revealed the expression of phenotypic molecules that have not been previously described for ILCs. Our analysis shows that human ILCs are highly heterogeneous cell types between individuals and tissues. It also provides a global, comprehensive, and detailed description of ILC heterogeneity in humans across patients and tissues.
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                Author and article information

                Contributors
                +43.1.4040051760 , lukas.kenner@meduniwien.ac.at
                +49.30.94062863 , stephan.mathas@charite.de
                Journal
                Leukemia
                Leukemia
                Leukemia
                Nature Publishing Group UK (London )
                0887-6924
                1476-5551
                28 March 2018
                28 March 2018
                2018
                : 32
                : 9
                : 1994-2007
                Affiliations
                [1 ]ISNI 0000 0001 1014 0849, GRID grid.419491.0, Max-Delbrück-Center for Molecular Medicine, ; 13125 Berlin, Germany
                [2 ]ISNI 0000 0001 2218 4662, GRID grid.6363.0, Hematology, Oncology, and Tumor Immunology, , Charité—Universitätsmedizin Berlin, ; 12200 Berlin, Germany
                [3 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Institute of Clinical Pathology, , Medical University of Vienna, ; Vienna, Austria
                [4 ]European Research Initiative on ALK-Related Malignancies (ERIA), Cambridge, UK
                [5 ]ISNI 0000 0000 9323 8675, GRID grid.418217.9, German Rheumatism Research Centre, , German Rheumatism Research Centre (DRFZ), A Leibniz Institute, ; 10117 Berlin, Germany
                [6 ]ISNI 0000 0001 2218 4662, GRID grid.6363.0, Medical Department I, , Charité—Universitätsmedizin Berlin, ; 12200 Berlin, Germany
                [7 ]ISNI 0000 0001 2218 4662, GRID grid.6363.0, Institute of Pathology, , Charité—Universitätsmedizin Berlin, ; 10117 Berlin, Germany
                [8 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, German Cancer Consortium (DKTK), , German Cancer Research Center (DKFZ), ; 69120 Heidelberg, Germany
                [9 ]ISNI 0000000122199231, GRID grid.214007.0, The Scripps Research Institute, ; Jupiter, FL 33458 USA
                [10 ]ISNI 0000 0001 2336 6580, GRID grid.7605.4, Department of Molecular Biotechnology and Health Sciences, Center for Experimental Research and Medical Studies, , University of Torino, ; Torino, Italy
                [11 ]ISNI 0000 0001 2165 8627, GRID grid.8664.c, NHL-BFM Study Centre and Department of Paediatric Haematology and Oncology, , Justus-Liebig-University, ; Giessen, Germany
                [12 ]ISNI 0000 0001 2218 4662, GRID grid.6363.0, Department of Nephrology, , Charité—Universitätsmedizin Berlin, ; 12200 Berlin, Germany
                [13 ]ISNI 0000 0000 9259 8492, GRID grid.22937.3d, Institute of Pharmacology, Center for Physiology and Pharmacology, , Medical University Vienna, ; Vienna, Austria
                [14 ]ISNI 0000 0004 0436 8814, GRID grid.454387.9, Ludwig Boltzmann Institute for Cancer Research (LBI-CR), ; Vienna, Austria
                [15 ]ISNI 0000000121885934, GRID grid.5335.0, Department of Pathology, , University of Cambridge, ; Cambridge, CB21QP UK
                [16 ]ISNI 0000 0004 0551 4246, GRID grid.16149.3b, Department of Medicine A, Albert-Schweitzer-Campus 1, , University Hospital Münster, ; 48149 Münster, Germany
                [17 ]Cluster of Excellence EXC 1003, Cells in Motion, 48149 Münster, Germany
                [18 ]ISNI 0000 0000 9686 6466, GRID grid.6583.8, University of Veterinary Medicine, ; Vienna, Austria
                [19 ]CBmed, Center for Biomarker Research in Medicine, 8010 Graz, Austria
                [20 ]ISNI 0000 0001 1014 0849, GRID grid.419491.0, Experimental and Clinical Research Center, a joint cooperation of Max-Delbrück-Center for Molecular Medicine and Charité - Universitätsmedizin Berlin, ; 13125 Berlin, Germany
                Author information
                http://orcid.org/0000-0002-8959-1083
                Article
                45
                10.1038/s41375-018-0045-9
                6127090
                29588546
                55d53462-1ae8-4f6d-9670-6c0c4928fa17
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. If you remix, transform, or build upon this article or a part thereof, you must distribute your contributions under the same license as the original. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/.

                History
                : 8 March 2017
                : 20 December 2017
                : 8 January 2018
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                © Springer Nature Limited 2018

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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