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      The Role of Activator Protein-1 (AP-1) Family Members in CD30-Positive Lymphomas

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          Abstract

          The Activator Protein-1 (AP-1) transcription factor (TF) family, composed of a variety of members including c-JUN, c-FOS and ATF, is involved in mediating many biological processes such as proliferation, differentiation and cell death. Since their discovery, the role of AP-1 TFs in cancer development has been extensively analysed. Multiple in vitro and in vivo studies have highlighted the complexity of these TFs, mainly due to their cell-type specific homo- or hetero-dimerization resulting in diverse transcriptional response profiles. However, as a result of the increasing knowledge of the role of AP-1 TFs in disease, these TFs are being recognized as promising therapeutic targets for various malignancies. In this review, we focus on the impact of deregulated expression of AP-1 TFs in CD30-positive lymphomas including Classical Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma.

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          Most cited references159

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          AP-1: a double-edged sword in tumorigenesis.

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            Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma.

            Classical Hodgkin lymphoma (cHL) and mediastinal large B-cell lymphoma (MLBCL) are lymphoid malignancies with certain shared clinical, histologic, and molecular features. Primary cHLs and MLBCLs include variable numbers of malignant cells within an inflammatory infiltrate, suggesting that these tumors escape immune surveillance. Herein, we integrate high-resolution copy number data with transcriptional profiles and identify the immunoregulatory genes, PD-L1 and PD-L2, as key targets at the 9p24.1 amplification peak in HL and MLBCL cell lines. We extend these findings to laser-capture microdissected primary Hodgkin Reed-Sternberg cells and primary MLBCLs and find that programmed cell death-1 (PD-1) ligand/9p24.1 amplification is restricted to nodular sclerosing HL, the cHL subtype most closely related to MLBCL. Using quantitative immunohistochemical methods, we document the association between 9p24.1 copy number and PD-1 ligand expression in primary tumors. In cHL and MLBCL, the extended 9p24.1 amplification region also included the Janus kinase 2 (JAK2) locus. Of note, JAK2 amplification increased protein expression and activity, specifically induced PD-1 ligand transcription and enhanced sensitivity to JAK2 inhibition. Therefore, 9p24.1 amplification is a disease-specific structural alteration that increases both the gene dosage of PD-1 ligands and their induction by JAK2, defining the PD-1 pathway and JAK2 as complementary rational therapeutic targets.
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              The regulation of AP-1 activity by mitogen-activated protein kinases.

              M Karin (1995)
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                28 March 2018
                April 2018
                : 10
                : 4
                : 93
                Affiliations
                [1 ]Ludwig Boltzmann Institute for Cancer Research, 1090 Vienna, Austria; Ines.Garces@ 123456lbicr.lbg.ac.at
                [2 ]Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria; Sabine.Lagger@ 123456vetmeduni.ac.at
                [3 ]Clinical Institute of Pathology, Medical University of Vienna, 1090 Vienna, Austria; huan-chang.liang@ 123456meduniwien.ac.at (H.-C.L.); Olaf.merkel@ 123456meduniwien.ac.at (O.M.)
                [4 ]Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB21QP, UK; sdt36@ 123456cam.ac.uk
                Author notes
                [†]

                Co-first authors.

                [‡]

                Co-last authors.

                Author information
                https://orcid.org/0000-0003-2612-3714
                https://orcid.org/0000-0002-8439-4507
                Article
                cancers-10-00093
                10.3390/cancers10040093
                5923348
                29597249
                c2f5880d-f522-40fa-87c7-53c4260f5a70
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 22 February 2018
                : 25 March 2018
                Categories
                Review

                activator protein-1 (ap-1),transcription factors (tfs),anaplastic large cell lymphoma (alcl),cd-30,classical hodgkin lymphoma (chl),peripheral t-cell lymphoma (ptcl)

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