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      VLA-4 Expression and Activation in B Cell Malignancies: Functional and Clinical Aspects

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          Abstract

          Lineage commitment and differentiation of hematopoietic cells takes place in well-defined microenvironmental surroundings. Communication with other cell types is a vital prerequisite for the normal functions of the immune system, while disturbances in this communication support the development and progression of neoplastic disease. Integrins such as the integrin very late antigen-4 (VLA-4; CD49d/CD29) control the localization of healthy as well as malignant B cells within the tissue, and thus determine the patterns of organ infiltration. Malignant B cells retain some key characteristics of their normal counterparts, with B cell receptor (BCR) signaling and integrin-mediated adhesion being essential mediators of tumor cell homing, survival and proliferation. It is thus not surprising that targeting the BCR pathway using small molecule inhibitors has proved highly effective in the treatment of B cell malignancies. Attenuation of BCR-dependent lymphoma–microenvironment interactions was, in this regard, described as a main mechanism critically contributing to the efficacy of these agents. Here, we review the contribution of VLA-4 to normal B cell differentiation on the one hand, and to the pathophysiology of B cell malignancies on the other hand. We describe its impact as a prognostic marker, its interplay with BCR signaling and its predictive role for novel BCR-targeting therapies, in chronic lymphocytic leukemia and beyond.

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          Integrin ligands at a glance.

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            Integrin-based therapeutics: biological basis, clinical use and new drugs

            Integrins are activatable molecules that are involved in adhesion and signalling. Of the 24 known human integrins, 3 are currently targeted therapeutically by monoclonal antibodies, peptides or small molecules: drugs targeting the platelet αIIbβ3 integrin are used to prevent thrombotic complications after percutaneous coronary interventions, and compounds targeting the lymphocyte α4β1 and α4β7 integrins have indications in multiple sclerosis and inflammatory bowel disease. New antibodies and small molecules targeting β7 integrins (α4β7 and αEβ7 integrins) and their ligands are in clinical development for the treatment of inflammatory bowel diseases. Integrin-based therapeutics have shown clinically significant benefits in many patients, leading to continued medical interest in the further development of novel integrin inhibitors. Of note, almost all integrin antagonists in use or in late-stage clinical trials target either the ligand-binding site or the ligand itself.
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              Immune surveillance in the central nervous system

              Despite being protected by the blood-brain barrier, the CNS must constantly be monitored for insult or pathogen invasion. In this review, the authors illustrate the molecular and cellular players that preside over this surveillance of the brain and spinal cord.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                23 March 2020
                March 2020
                : 21
                : 6
                : 2206
                Affiliations
                [1 ]Department of Internal Medicine I, Medical Center and Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; andrea.haerzschel@ 123456uniklinik-freiburg.de
                [2 ]Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; zucchetto.soecs@ 123456cro.it (A.Z.); vgattei@ 123456cro.it (V.G.)
                Author notes
                [* ]Correspondence: tanja.hartmann@ 123456uniklinik-freiburg.de ; Tel.: +49-761-27071511
                Author information
                https://orcid.org/0000-0002-0377-7179
                Article
                ijms-21-02206
                10.3390/ijms21062206
                7139737
                32210016
                82d43303-3c17-48a1-9977-7c22fa40e39e
                © 2020 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
                : 14 February 2020
                : 20 March 2020
                Categories
                Review

                Molecular biology
                lymphoma,leukemia,tumor microenvironment,integrin,b cell differentiation,adhesion,b cell receptor,therapy,bruton’s tyrosine kinase,cd49d,chronic lymphocytic leukemia,cll

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